`cynert review of hematology.
`2, no. 5 (Oct. 2009)
`eneral Collection
`EX52NUN
`9009-11-23 06:04:59
`
` Expert Review of
` O >
`
`4 a O
`F < a
`- = >
`
`pert ReviewsLtd
`
`N 1747-4086
`
`October 2009 vol. 2 no. 5
`
`
`
`Hematology
`
`EpDITORIAL
`Individualizing treatment for Waldenstrom’s macroglobulinemia
`
`Drua PROoFILes
`Clinical activity of laromustine (Onrigin™) in hematologic malignancies
`Bosutinib: a dual SRC/ABL kinaseinhibitor for chronic myeloid leukemia
`
`Prophylaxis of venous thrombosis in congenital antithrombin deficiency
`Meetinc REPorT
`2nd International Congress on Leukemia, Lymphomaand Myeloma
`Key PaPrer EVALUATION
`Recombinant erythropoiesis-stimulating agents and cancer mortality
`
`REVIEWS
`Adoptive T-cell therapy for B-cell malignancies
`Biology and treatmentoffollicular lymphoma
`Prognostic tools in follicular lymphomas
`Prognostic molecular markers in myelodysplastic syndromes
`Noninvasive approach for the managementoffetus hemolytic disease
`Late complications after hematopoietic stem cell transplantation
`|
`EXPERT
`| REVIEWS
`
`Miltenyi Ex. 1011 Page 1
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`Miltenyi Ex. 1011 Page 1
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`

`

` October 2009
`
`517. Adoptive T-cell therapy for
`B-cell malignancies
`M Hudecek, LD AndersonJr, T Nishida
`& SR Riddell
`.
`533 Biology and treatment of
`follicular lymphoma
`* Safety concernshalt trial of sildenafil in sickle cell
`PP Piccaluga, MR Sapienza, C Agostinelli,
`+ Anite iveland Ieakeiits Gelieineseausrced
`
`* Helixate® approved for hemophilia A children C Saaramoso, C Mannu.ESabattini
`* Transfusion confusionstill abounds
`gfe 08 doris a Mes
`an,
`* Double award glory for leukemia pioneer
`PL Zinzani & SAPileri
`Drug Profiles
`549 Prognostic tools in follicular lymphoma
`a
`_
`S$ Luminari, MC Cox, A Montanini
`481 Clinical activity of
`& M Federico
`laromustine (Onrigin™)in
`hematologic malignancies
`Prognostic molecular markers in
`Y Alvarado, R Swords, KR Kelly & FJ Giles
`myelodysplastic syndromes _
`_.
`.
`J Neukirchen, R Haas & U Germing
`489 Bosutinib: a dual SRC/ABL kinase
`;
`inhibitor for the treatment of chronic
`577 Noninvasive approachfor the
`myeloid leukemia
`managementof hemolytic disease of
`G Keller, P Schafhausen & TH Brummendorf
`the fetus
`.
`.
`.
`§ Illanes & P Soothill
`499 Antithrombin-a for the prophylaxis of
`venous thrombosis in congenital
`Late complications after hematopoietic
`antithrombin deficiency
`stem cell transplantation
`A Fyfe & RC Tait
`A Tichelli, A Rové, J Passweg, CP Schwarze,
`MTV Lint, M Arat & G Socié
`
`Expert Review of
`
`Hematology
`
`Expert Rev. Hematol. 2(5)
`
`Editorial
`
`Reviews
`
`Individualizing treatment for
`Waldenstrom’s macroglobulinemia
`J Stedman, A Roccarorene & IM Ghobrial
`
`Newsin brief
`
`563
`
`583
`
`473
`
`477
`
`509
`
`513
`
`Meeting Report
`.
`2nd International Congress on
`Leukemia, Lymphoma and Myeloma
`M Arat, GH Ozsan, MN Yenerel, M Cetin
`& M Ozcan
`.
`Key Paper Evaluation
`Two faces for Janus: recombinant
`humanerythropoiesis-stimulating
`
`Appendices
`602 Glossary
`604
`Indices
`609 Acknowledgements
`610 Author Guidelines
`Calendar
`
`|
`EXPERT
`agents and cancer mortality
`
`alia,NFreg REVIEWS
`R Addeo, M Caraglia, N Frega & SD Prete
`
`www.expert-reviews.com
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`© 2009 Expert ReviewsLtd
`
`ISSN 1747-4086
`Miltenyi Ex. 1011 Page 2
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`Miltenyi Ex. 1011 Page 2
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`

`

` REVIEWS
`aee | os
`
`Expert Review of
`
`Hematology
` _ TheEditorialBoardis drawnfromthe PetFoc in eeRL Cy
`
`ete
`
`LambertenghiDeliliers G, Univ. of Milan, Italy
`
`Leen AM,Baylor College of Med., TX, USA
`
`Machin SM,Univ. College London, UK
`
`MurphyM,National Blood Service, UK
`
`O’Connor 0, Columbia Univ. Med. Ctr, NY, USA
`
`Orlowski RZ, MD Anderson CancerCtr., TX, USA
`
`PalmbladJ, Karolinska Institutet, Sweden
`
`Pileri S, Bologna Univ. Schoolof Med., Italy
`
`Prentice A, Royal Free Hospital, UK
`
`RichardsonP, Dana Farber CancerInst., MA, USA
`
`Roboz GJ, Weill Medical College NY, USA
`
`Schiffer C, Barbara Ann Karmanos CancerInst., USA
`
`Stone RM,Dana Farber CancerInst., MA, USA
`
`HochhausA, Univ. of Heidelberg, Germany
`
`Valent P, Med. Univ. of Vienna, Austria
`
`Bei)cae
`Oc
`ere Mata
`BelletByler(ogee
`Saree Enyce
`
`Aledort LM, MtSinai School of Med., NY, USA
`=
`——
`ahead oo Aplan P, National CancerInstitute, MD, USA
`
`. eget oo Ataga K, Univ. ofNorth Carolina, NC, USA
`
`ack:
`Meleelei(erel|e) eee
`:
`: ss oe B
`Byrd JC, The Ohio State Univ., OH, USA
`
`Victoria Lane—
`oo
`
`Cee ee
`Cappellini MD, Univ. of Milan, Italy
`Commissioning Editor
`
`CastamanG, San Bortolo Hospital, Italy
`ee
`a8
`Andy Palmer
`
`rtes J, MD Anderson CancerCtr., TX, USA
`ety4 eter hele
`Co!
`A
`Ut
`oo
`ak
`
`Dimopoulos MA,Univ. of Athens, Greece
`| Tarek Kattan
`
`Dreyling M, Univ. of Munich, Germany
`i
`aelarelBe Engert A,Univ. Hosp. of Cologne, Germany
`
`adeltll
`Giles FJ, Cancer Ther. & Res. Center, TX, USA
`
`Be
`Grever M,The OhioState Univ., OH, USA
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`Managing
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`HarousseauJ-L, Ctr. Hosp. Univ. Hétel-Dieu, France
`geraL) Editor
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`* Marrowfailure syndromes
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`Neutropenia
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`Platelet disorders
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`Advanced molecular research techniques have transformed hematology in recent years. With im-
`proved understanding of hematologic diseases, we now have the opportunity to research and evaluate
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`including stem cell transplantation. Further agtances in our knowledge regarding the formation and
`function of blood cells and blood-forming
`| Coverage includes:
`tissues should ensue, and it will be a ma-
`¢ Hematological malignancies
`jor challenge for hematologists to adopt
`e Anemias
`these new paradigms and develop integrat-
`|* Thrombosis and hemostasis
`ed strategies to define the best possible
`| Bone marrow and hematopoietic stem cell transplantation
`patient care.
`Expert Review of Hematology provides—« |mmunodeficiency syndromes
`commentary and analysis to elucidate best
`« Autoimmune diseases
`clinical practice in hematology and to trans-
`late advances in research — in areas such as
`immunology, stem cell research, and cell and
`gene therapy — into the clinical context.
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`Transfusion medicine
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`
`|
`EXPERT
`| REVIEWS
`
`Adoptive T-cell therapy for
`B-cell malignancies
`
`Expert Rev. Hematol. 2(5), 517-532 (2009)
`
`The success of allogeneic hematopoietic cell transplantation (HCT) for B-cell malignancies is
`Michael Hudecek,
`evidence that these tumors can beeliminated by T lymphocytes. This has encouraged the
`Larry D Anderson Jr,
`developmentof specific adoptive T-cell therapy, both for augmenting the anti-tumoreffect of
`Tetsuya Nishida and
`HCT and for patients not undergoing HCT.T cells that are capable of recognizing antigens
`expressed on malignantBcells may be recruited from the endogenousrepertoire or engineered
`Stanley R Riddell’
`to express tumor-targeting receptors. Critical insights into the qualities of T cells that enable
`‘Authorfor correspondence
`their persistence and function in vivo have been derived, and obstacles to effective T-cell-
`Fred Hutchinson Cancer
`mediated tumoreradication are being elucidated. These advancesprovide the tools to translate
`Research Center, 1100 Fairview
`Avenue N, D3-100,Seattle,
`adoptive T-cell transferinto reliable clinical therapies.
`WA 98109, USA
`Tel.: +1 206 667 5249
`Fax: +1 206 667 7983
`sriddell@ fherc.org
`
`Keyworps: adoptive T-cell therapy * allogeneic hematopoietic cell transplantation * central memory T cell
`* chimeric antigen receptor * immunoglobulin idiotype * graft-versus-host disease * graft-versus-tumor effect
`* minor histocompatibility antigen * T-cell receptor « tumor antigen
`
`although GVTactivity cannotyet be reproduc-
`Thepotentialto use immune-basedtherapies for
`ibly separated from graft-versus-host disease
`human malignanciesis attractive because of the
`(GVHD) [4-7]. The demonstration that B-cell
`specificity of antibody and T-cell recognition.
`tumors are recognized by T cells has provided
`The most profound advances have been made
`optimism that donor T cells specific for tumor-
`in the developmentofantibodies as therapeutics,
`associated antigens mightbeisolated, expanded
`and several monoclonalantibodies that recog-
`and administered to the patient to augmentthe
`nize molecules on the surface of cancercells are
`GVTeffect; or that autologous T cells might
`being used in humancancertherapy. Antibodies
`be elicited or engineered to recognize tumor-
`that target CD20 and CD52 are now routinely
`associated antigens, without the need for allo-
`employed in standard therapeutic regimens for
`geneic HCT. Engineering of tumor reactive
`subsetsofpatients with B-cell malignancies (1-3).
`T cells can be accomplished by gene transfer
`The developmentofeffective T-cell therapy for
`techniques that introduce a T-cell receptor
`human malignancyeither through vaccination
`(TCR) with specificity for peptide fragments of
`or by adoptive T-cell transfer, whichrefers to the
`intracellular proteins displayed on class I and
`isolation, expansion and reinfusion of tumor-
`class II MHC molecules expressed by the tumor,
`reactiveTcells, has been substantially morechal-
`or a chimeric antigen receptor (CAR) that con-
`lenging. The difficulties in developing T-cell-
`sists of a single-chain antibody fragment(scFv)
`based immunotherapies are due,in part, to the
`specific for a B-cell surface molecule linked to
`inability ofcurrent vaccines to reproduciblyelicit
`the ¢-chain ofthe CD3/TCR complex {8,9}. This
`effective tumor-reactive T-cell responses, and the
`review will discuss the rationale and theoretical
`complexity of deriving and expanding tumor-
`framework for developing adoptive T-cell ther-
`reactive T cells ex vive that have the capacity to
`apy for B-cell malignancies, the obstacles that
`persist and function following adoptive transfer.
`have been encountered, and the directions that
`Despite these obstacles, the exquisite ability of
`are currently being takenforclinicaltranslation.
`T cells to distinguish diseased from normalcells
`has encouraged the continued investigation of
`GVT effect of allogeneic HCT in
`strategies to employT cells as therapeutic agents.
`B-cell malignancies
`Thereis evidence from allogeneic hematopoi-
`Allogeneic HCT provides a potentially curative
`etic cell transplantation (HCT) that advanced
`therapy for a variety of hematologic malignan-
`B-cell malignancies are susceptible to a T-cell-
`cies, including many B-cell tumors. Originally,
`mediated graft-versus-tumor (GVT) effect,
`enEEEEEEEE
`
`
`
`www.expert-reviews.com
`
`10.1586/EHM.09.47
`
`ISSN 1747-4086
`© 2009 Expert Reviews Ltd
`Miltenyi Ex. 1011 Page 6
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`517
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`Miltenyi Ex. 1011 Page 6
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`

`_ Hudecek, Anderson, Nishida & Riddell
`
`
`
`
`allogeneic HCT was developed as a methodofrescuing patients
`from thelethaltoxicity ofhigh doses ofmyeloablative chemoradio-
`therapy administered to achieve greater tumor-cell killing than
`could be achieved with conventional doses of chemotherapy [10],
`and was used as a treatmentoflast resort for patients with refrac-
`tory leukemia, including B-lineage acute lymphoblastic leukemia
`(B-ALL). Consistent with the prediction from murine models,
`that immunerecognition oftumorcells could contribute to tumor
`eradication, human allogeneic HCTfor B-ALL was accompanied
`by a T-cell mediated GVT effect[1-13]. AGVTeffect ofallogeneic
`HCThassubsequently been confirmedin other B-cell malignan-
`cies, including chronic lymphocytic leukemia (B-CLL), multiple
`myeloma (MM)and non-Hodgkin lymphoma (NHL)(14-18). The
`myeloablative chemotherapy regimen contributes substantially to
`tumor control butit is now realized that the curative potential
`of this procedure is a result of the immunologic elimination of
`malignantcells. This is evident from the strikingly lower relapse
`rate and increased leukemia-free survivalrate in patients receiving
`an allogeneic HCT compared with syngeneic HCT [12,13]. There
`are several factors that limit the success of allogeneic HCT and
`efforts to improve outcomeare focused on reducingtoxicity dueto
`conditioning and GVHD,and augmenting the GVTeffect (Taste 1).
`
`|
`
`of GVHDremains a major complication associated with the use
`of donor lymphocytes. Although some patients receiving DLI
`achieve complete remissions in the absence of clinically evident
`GVHD,most respondingpatients develop acute and chronic
`GVHDsuggesting the antigens that are recognized on tumor
`cells are often shared with othertissues. The risk of GVHD can
`be attenuated in a subsetofpatients by using gradually escalating
`doses ofDLIbutthis strategy is mosteffectively applied in slowly
`progressive malignancies [24-26].
`
`Reduced-intensity conditioning regimensfor
`allogeneic HCT
`Allogeneic HCT employing myeloablative conditioning is
`restricted to younger and medically fit patients to avoid exces-
`sive mortality from toxicities related to chemoradiotherapy. The
`median ageat diagnosis for B-CLL and MMis over 60 years and
`these patients often have comorbidities due to their age, underly-
`ing malignancyor prior chemotherapy. This limitation to the use
`ofallogeneic HCT was overcomeby the development of reduced-
`intensity conditioning (RIC) regimens that use low doses of
`chemoradiotherapy to immunosuppresstherecipientsufficiently
`to preventrejection ofthe donorstem and T-cell graft, and enable
`a GVTeffect to mediate tumoreradication(27,28). RIC-HCT has
`been effective in several indolent B-cell malignancies, including
`B-CLL, MMand lymphoma,although aggressive lymphoma and
`B-ALLare less responsive [5-729]. Similar to the observations made
`in patients receiving myeloablative HCT, the anti-tumoreffi-
`cacy ofRIC-HCTishighly correlated with GVHD, which often
`requires long-term immunosuppressive therapy and is a major
`cause of morbidity and mortality. Therefore, the development
`of approaches that could be incorporated with HCT, such as the
`adoptive transfer of T cells that can specifically target antigens
`that are preferentially or selectively expressed on the tumor to
`augment the GVT effect without inducing GVHD,is a high
`priority of current research efforts.
`
`Donor lymphocyteinfusions for B-cell malignancies
`A critical role for donor T cells in the GVT effect was dem-
`onstrated by studies by Kolb et al. who investigated the use of
`donor lymphocyte infusions (DLIs) in patients with leukemia
`relapse after allogeneic HCT {19]. Durable complete remissions
`were achieved in 10-40%ofpatients with B-ALL, B-CLL, MM
`and lymphomas (20-22). This compares with responserates ofup to
`70%in patients with relapsed chronic myeloid leukemia (CML)
`andit has been hypothesized that the superior ability ofCMLcells
`to differentiate into antigen presenting dendritic cells (DCs) and
`prime anti-tumor T-cell responses may be responsible for these
`differences in outcome [19,23]. To improve the outcomeofpatients
`with B-cell malignancies receiving DLIs, strategies such as the
`administration of pre-DLI chemotherapy or the use of ex vivo-
`activated donor lymphocytesare being explored. The induction
`
`
`
`Table 1. Factors that limit the success of allogeneic
`hematopoietic cell transplantation.
`*
`
`Toxicity due to the Employ reduced-intensity
`conditioning
`conditioning regimens
`regimen
`Graft-versus-
`host disease
`
`Minor histocompatibility antigens as targets for the
`GVTeffect
`In the context of an allogeneic HCT from an HLA-identical
`donor, T-cell recognition of minor histocompatibility antigens
`(minor H antigens)is responsible for GVHDandhas been impli-
`cated in the GVT effect. Minor H antigens result from genetic
`polymorphisms between the HCTrecipient and the correspond-
`ing HLA-identical stem cell donor (30). The most common mecha-
`nism for generating a minor H antigen is a non-synonymous
`single nucleotide polymorphism (SNP) that results in a peptide
`presented by HLA-moleculeson recipient cells to which the HLA-
`identical donoris not tolerant and can be recognizedas ‘non-self”
`by donor CD8* and CD4*T cells (31). Other mechanismsfor gen-
`erating minor H antigensincludingalternativesplicing of peptide
`fragments, and differential protein expression as a consequence
`of gene deletion have also been identified [32,33].
`Reduced-intensity conditioning-HCTrelies almost exclusively
`on immuneelimination of tumorcells and provides an opportu-
`nity to dissectthe specificity of tumor-reactive T cells that develop
`
`
`Improve drug regimensfor
`immunosuppression
`Targeted suppression ofalloreactive T-cell
`activation or function
`Remove alloreactive T cells from the donor
`stem cell graft
`Adoptive transfer of tumor-reactive T cells
`Vaccinationto elicit tumor-reactive T-cell
`responsesin vivo
`
`Tumorrelapse
`
`518
`
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`
`
`
`Adoptive T-cell therapy for B-cell malignancies
`
`with the panel of minor H antigens that are presently known,
`since only a few patients could actually benefit from this strategy.
`This obstacle will only be resolved by the discovery of additional
`minor H antigens. The HapMapproject has identified over 10°
`SNPs in the human genome that confer amino acid sequence
`changesin codingregionsandthis database has enabledtheuse of
`genomeassociation studies for minor H antigen discovery, which
`should rapidly expand the number of minor H antigensat our
`disposal(41). A secondobstacle for targeting minor H antigens is
`the need to derive and expand minor H antigen-specific T cells
`from the donorfor adoptive transfer in every case. A potential
`solution discussedlaterin this review is the isolation ofTCRgenes
`from high-avidity minor H antigen-specific T cells, construction
`ofgenetransfer vectors and engineeringofprimary donor T cells
`for transfer in suitable patients.
`
`Adoptive immunotherapywith T cells specific for
`nonpolymorphic tumor-associated antigens
`Ideally, nonpolymorphic antigensexpressed on B-cell tumors could
`be targeted using autologousT cells to circumventthe need to finda
`suitable donorfor allogeneic HCT and the complications associated
`with HCT.In ouranalysis ofT-cell responses that developed after
`
`Leukemia/tumorcell
`
`Epithelialcell
`
`
`
`after HCT, and identify minor H or tumor-associated antigens
`that are the targets of the GVTresponse.In a studyat the Fred
`Hutchinson Cancer Research Center (FHCRC) we analyzed the
`temporalkinetics andspecificity ofT cells that develop after non-
`myeloablative-HCT for B-CLLbecause large numbers of tumor
`cells could be stored pre-transplant andusedto assess recognition
`by donor T cells that developed in therecipient post-transplant
`34]. We found that CD8* and CD4* T-cell responses directed
`against minor H antigens expressed by B-CLL developedin all
`patients that achieved sustained tumorregression andcorrelated
`with the clearance of tumorcells from peripheral blood, bone
`marrow and lymph nodes. By contrast, patients with progres-
`sive B-CLL after HCT failed to develop T cells that recognized
`leukemic cells, even though they often developed GVHD,sug-
`gesting the failure to eradicate the tumor in these patients was
`because alloreactive T cells only recognized antigens that were
`not shared by target tissues of GVHD and the tumor (Fiver 1)
`[34]. The kinetics with which tumor-reactive T cells developed in
`respondingpatients after RIC-HCTvaried from several weeksto
`1 year, however onceestablished,these T cells persisted long-term,
`indicating that immunologic memory wasestablished. Analysis of
`the specificity ofCD8° T cells that recognized B-CLLin patients
`that achieved a complete remission dem-
`onstrated that multiple minor H antigens
`were being targeted, including those that
`were broadly expressed on both