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5.39Feasibility Analysis of Non-myeloablativeAllogeneic Stem Cell Transplantation inPatients with Chronic Lymphocytic Leukemiaand 17p DeletionYvonne Hsu, Rima M. Saliba, Grace-Julia Okoroji,Susa O’Brien, Alessandra Ferrajoli, Lynne Abruzzo,Richard Champlin, Michael Keating, Issa F. KhouriMD Anderson Cancer Center

Background: Deletion of 17p (17p–) is the principal predictor ofpoor outcome in chronic lymphocytic leukemia (CLL) patients afterconventional chemotherapy. Several reports have shown better out-comes with non-myeloablative allogeneic stem cell transplantation(NST). However, questions have been raised as to the relevance ofNST, in particular, the extent that various selection biases lead toselection of only the ‘best’ patients for this procedure. Purpose: Ourprimary goal was to update our NST experience with 17p–, andreport how often patients underwent transplantation and, within thelimits of a retrospective analysis, the reasons for not undergoingtransplantation. Methods: We reviewed NST outcomes for 17p–CLL patients transplanted between 2005 (when FISH became rou-tinely performed at our institution) and 2010. Given the poor out-come after conventional fludarabine, cyclophosphamide, and ritux-imab (FCR) therapy, a diligent effort was started by the leukemiaservice in 2007 to refer patients to transplant sooner rather than later.Therefore, in a subanalysis, we reviewed the number of 17p– CLLpatients who were referred to the transplant consult service from2007 and assessed the reasons for no transplant. Prognostic factorswere evaluated using Cox’s regression model. Multivariate analysiswas not possible given sample size limitations. Results: Outcome ofNST in 17p– CLL patients: Twenty-six patients were transplanted atour institution between 2005 and 2010. The median age was 56years (range 37–73 years). At NST, 15 patients (58%) had �2-mi-croglobulin (�2m) � 3; 21/24 patients (87%) had Binet stage B/Cdisease; 4 patients (15%) had Richter’s syndrome; 16/25 patients(64%) were FDG-avid; the median number of prior chemotherapieswas 4 (range 2–14); and 14 patients (54%) had refractory disease.Thirteen patients (50%) had complex cytogenetic abnormalities (inaddition to 17p–). IGVH was unmutated in 11/12 patients (92%)tested and 14/15 (93%) were ZAP-70 positive. Prior to their trans-plantation, 24 patients (92%) were exposed to FCR, 11 (42%) toFCR plus alemtuzumab or oxaliplatin, 7 (27%) to hyper-CVAD,and 17 (65%) to alemtuzumab. With a median follow-up of 18months (range 3–60 months), 2-year overall survival (OS) and pro-gression-free survival (PFS) rates were 62% and 38%, respectively.On univariate analysis, determinants of outcomes included diseasestatus, �2m at NST, and year of transplant. All but 1 patient withchemosensitive disease had �2m � 4, compared with 50% of pa-tients with chemoresistant disease. Chemosensitivity was associatedwith significantly higher PFS (73% vs 12%, p � 0.02; Figure) and atrend toward higher OS (91% vs 45%, p � 0.09). PFS was alsoignificantly higher for transplants performed after 2007 (44% vs0%, p � 0.03). �2m � 4 was associated with lower 18 month OS

36% vs 71%, p � 0.05) in chemoresistant patients, but did not

Clinical Lymphoma, Myeloma & Leukemia Supplement October 2011

ignificantly impact PFS (38% vs 14%, p � 0.5). Two years’ fol-ow-up was not reached for �2m � 4 in this group. Transplantconsults and transplantation rate: Between September 2007 andMarch 2010, 59 patients with 17p– CLL received a transplant serviceconsult. Twenty of these patients (34%) had received a transplant atthe time of this analysis, whereas 39 (66%) had not. Reasons for notreceiving transplants included: (1) death with salvage pre-transplantchemotherapy (n � 14, 36%); (2) patient and/or physician becameuninterested after achieving a good response to salvage chemother-apy (n � 14, 36%); (3) lost to follow-up after the initial consultation(n � 3, 8%); (4) age � 75 years (n � 2, 5%); (5) insurance denialn � 3, 8%); (6) no donor (n � 1, 2%); and (7) other (n � 2, 5%).onclusions: NST is plausibly more effective in 17p– CLL patientshen recipients have chemosensitive disease. If, as suggested by our

nalysis, at most 34% of patients receive this procedure, methods toxtend the applicability of transplant are needed. Perhaps the mostffective method would be to use NST as consolidation after annitial response to conventional chemotherapy. Such a strategyould allow more patients to have chemosensitive disease at NST,

nd would decrease the death rate in heavily pre-treated patientsuring pre-transplant cytoreductive therapy.

5.40Rituximab Maintenance in Patients withChronic Lymphocytic Leukemia after First-LineTreatment with Rituximab plus Fludarabine,Cyclophosphamide, and Mitoxantrone: FinalResults of a Multicenter Phase II Trial onBehalf of the Spanish CLL Study Group (GELLC)Francesc Bosch,1 Pau Abrisqueta,2 Neus Villamor,3

María José Terol,4 Eva González-Barca,5 Marcos

Abstract 5.39: Progression-Free Survival by Disease Status atTransplant

0 10 20 30 40 50 60 70Months Post Transplant

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González,6 Christelle Ferrà,7 Eugenia Abella,8 Julio

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Abstracts

Delgado,9 Jose A. Garcia-Marco,10 YolandaGonzalez,11 Felix Carbonell,12 Secundino Ferrer,13

Encarna Monzo,14 Isidro Jarque,15 Ana Muntanola,16

Mireia Constants,17 Lourdes Escoda,18 Emiliontserrat19

1Department of Hematology, Hospital Vall d’Hebron, on behalf of

the Spanish Group of CLL (GELLC), Barcelona, Spain; 2Department

of Hematology, Hospital Vall d’Hebron, Barcelona, Spain;3Department of Pathology, Hospital Clinic, Barcelona, Spain;4Department of Hematology, Hospital Clínico Universitario de

Valencia, Valencia, Spain; 5Department of Hematology, Institut

Català d’Oncologia, L’Hospitalet de LLobregat, Spain; 6Department

of Hematology, University Hospital of Salamanca, Salamanca,

Spain; 7Department of Hematology, University Hospital Germans

Trias y Pujol, Badalona, Spain; 8Department of Hematology,

Hospital del Mar, Barcelona, Spain; 9Department of Hematology,

Hospital de la Santa Creu y Sant Pau, Barcelona, Spain;10Department of Hematology, Hospital Universitario Puerta de

Hierro, Madrid, Spain; 11Department of Hematology, Dr. Josep

Trueta, Girona, Spain; 12Department of Hematology, Hospital

General Universitario, Valencia, Spain; 13Department of

Hematology, Hospital Universitario Dr Peset, Valencia, Spain;14Department of Hematology, Hospital Arnau de Vilanova, Valencia,

Spain; 15Department of Hematology, Hospital Universitario La Fe,

Valencia, Spain; 16Department of Hematology, Hospital Mutua de

Terrassa, Terrassa, Spain; 17Hematology, Althaia, Xarxa Assistencial

de Manresa, Spain; 18Hematology, Hospital Universitari Joan XXIII,

Tarragona, Spain; 19Institute of Hematology and Oncology,

Department of Hematology. Hospital Clínic, IDIBAPS, Barcelona,

Spain

In November 2005, we launched a Phase II clinical trial aimed atinvestigating the feasibility of, response to, and toxicity of rituximab,fludarabine, cyclophosphamide, and mitoxantrone (R-FCM), givenalong with granulocyte colony-stimulating factor ( G-CSF), followedby rituximab as maintenance therapy. The first part of the study(R-FCM ‘induction’ therapy), which resulted in an overall responserate of 93% and a complete response (CR) rate of 82% (46% mini-mal residual disease [MRD]-negative CR), has already been pub-lished.1 Here, we present the final results of the maintenance therapythat was initiated 3 months after R-FCM induction and consisted ofrituximab 375 mg/m2 every 3 months for 2 years (up to 8 cycles).

atients receiving � 4 cycles of maintenance therapy were evaluatedor response, including bone marrow examination and MRD assess-ent in peripheral blood and bone marrow by 4-color flow cytom-

try. Patients in whom rituximab maintenance was prematurely in-errupted (� 4 cycles) because of toxicity were considered as failures.ixty-four patients (median age 60 years, 70% male) received a me-ian of 8 cycles of maintenance therapy (range 1–8) and 76% ofatients completed the entire planned treatment. Treatment waselayed because of insufficient hematologic recovery in 9 cycles (2%)nd because of non-hematologic toxicity in 4 cycles (0.8%). Toxicityas mainly hematologic, with neutropenia in 31.3% of cycles (grade/4 in 8.5%), thrombocytopenia in 4.6%, and anemia in 1.2%. Athe end of maintenance therapy, 45% of patients had low immuno-

lobulin (Ig)A serum levels, 37% had low IgG, and 66% had low i

C

gM. Sixteen patients experienced grade 3/4 infectious episodes, in-luding 9 cases of pneumonia, 2 febrile neutropenia, 1 appendicitis,myositis, 1 herpes zoster, and 1 cerebral abscess. Two patients diedue to multifocal leukoencephalopathy and hemophagocytic syn-rome, respectively. After rituximab maintenance therapy, 40.6% ofatients were in MRD-negative CR, 40.6% were in CR, 7.9% weren partial remission (PR), and 10.9% were considered failures (dis-ase progression in 2 patients, severe neutropenia in 3, infectiousoxicity in 1, and death in 1). Among 35 patients who were in MRD-egative CR at the onset of maintenance therapy, 22 maintainedheir MRD-negative status at the end of maintenance, 9 (25.7%)witched from MRD-negative to MRD-positive (median time toonversion 44.7 months), and 4 failed to respond to treatment (Ta-le). Moreover, among 21 patients who achieved MRD-positive CRith the initial R-FCM treatment, 2 (9.5%) became MRD-negativepon rituximab maintenance, 17 (81%) continued in MRD-positiveR, 2 achieved a PR, and 2 failed to respond to maintenance therapy.inally, among 8 patients in PR after R-FCM induction, 4 patientschieved a CR (2 MRD-negative and 2 MRD-positive), 3 patientsontinued in PR, and 1 patient progressed (Table) after rituximabaintenance. In conclusion, R-FCM followed by rituximab as main-

enance therapy is a feasible and encouraging treatment that main-ains MRD-negative status in a high proportion of patients and im-roves the degree of response in more than 20% of patients.reatment toxicity is, however, not negligible. Further studies

hould help to clarify the role of maintenance therapy with rituximabn the management of patients with chronic lymphocytic leukemia.

Reference1. Bosch et al. J Clin Oncol 2009;27:4578.

5.41The Possible Origins of MyelodysplasticChanges Which Appear After Immunotherapyfor CLLA. Braester,1 L. Akria,1 C. Suriu,1 Mishchenko

lena,2 Y. Cohen,3 V. Sonkin3

1Institute of Hematology and; 3Institute of Pathology, Western

Galilee Hospital; 2Nahariya and Hematology Unit, Bnai Zion Medical

Center, Haifa, Israel

Background: Alemtuzumab (Campath-1H) (C) is a humanizedherapeutic monoclonal antibody (Mab) that recognizes cluster ofifferentiation (CD)52 antigen on chronic lymphocytic leukemiaCLL) cells. Adverse events related to C include hematologic toxicity.

causes transient cytopenia, which is usually resolved within 2onths of discontinuation of therapy. Myelodysplastic syndrome

MDS) is a clonal abnormality of the hematopoietic stem cells pre-enting with peripheral cytopenias in combination with a hyperplas-ic bone marrow. Most cases of MDS are idiopathic, but severalactors (antineoplastic alkylating agent, purine analog, ionizing radi-tion or benzene) have been shown to have a clear association with

DS etiology. Usually, therapy-related MDS (t-MDS) develops ateast 4 years after radiation/chemotherapy (usually involving alkylat-

ng agents, such as melphalan, cyclophosphamide or fludarabine).

linical Lymphoma, Myeloma & Leukemia Supplement October 2011 S271

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MDS post CLL treatment is not the rule, especially following ther-apy with Mab (such as C). Perhaps this is the time to recognize a newform of t-MDS – i-MDS (immunotherapy-induced MDS)? Casereports: Two CLL patients, heavily pretreated in the past (treatmentincluded fludarabine and cyclophosphamide), were in hematologicalremission for months after the last treatment with FCR. At time ofrelapse a bone marrow biopsy (BMB) was done, showing in bothcases a massive and diffuse infiltration of small lymphocytes. C ther-apy was started. A BMB repeated immediately after the end of treat-ment found no CLL in either case (as no monoclonal B populationwas found in peripheral blood and in bone marrow aspirate at im-munophenotyping analysis). But, surprisingly, a myelodysplasticpicture in the bone marrow was found. Discussion: Myelodysplasticfeatures following C treatment are a very rare event. Only 3 caseshave been described, but not in CLL patients (in T-cell lymphoma).The implication of C in MDS as an etiologic factor is supported bythe evidence that the BMB was without signs of myeloid toxicitiesjust prior to C therapy. Refuting this theory is the quick developmentof MDS after immunotherapy in these cases, in contrast with the wellknown t-MDS which develops slowly over years, in heavily pre-treated patients with inducing MDS chemotherapy. If C producedmyeloid toxicity during the therapy, we are unable to explain themechanism. Second possibility: The MDS clone exists when CLLrelapses, but the CLL-relapsed clone inhibits it; this is the reason thatwe did not see any sign of MDS in the bone marrow before the Ctherapy. Only after the eradication of CLL clone by C, does the MDSclone reappear. Third possibility: The MDS changes were presentbefore C treatment but intensive infiltration by CLL B-cells made itimpossible to distinguish these dysplastic changes. In one patient inthe pre-C treatment a myeloperoxidase stain of the bone marrow wasstrongly positive, demonstrating the presence of myeloid cells, hid-den by CLL infiltrates. Although we cannot conclude the presence ofmyelodysplastic changes in these cells, it is a possibility. Cytogeneticstudies, unfortunately not done, would have helped our supposition.It is premature to create a new term: i-MDS (immunotherapy in-duced myelodysplasia).

5.42The Heat Shock Protein 90 Inhibitor AUY922 isEffective in Combination with FludarabineAgainst CLL Cells Cultured on a CD40L-StromalLayer and Inhibits Their Activated/ProliferativePhenotypeGiles Best, Stephen MulliganNorthern Blood Research Centre, Kolling Institute, Royal North

Abstract 5.40 Response to Rituximab Maintenance

Response to R-FCM (n � 64)

CR MRD(�) (n � 35)

CR MRD(�) (n � 21)

PR (n � 8)

CR � complete response; MRD � minimal residual disease; PR � partial response; R-FCM, ri

Shore Hospital, St Leonards, NSW 2065, Australia

Clinical Lymphoma, Myeloma & Leukemia Supplement October 2011

Inhibition of heat shock protein 90 (Hsp90) has been proposed asa therapeutic option for high risk chronic lymphocytic leukemia(CLL) disease. We have investigated the effects of the novel Hsp90inhibitor, AUY922 (Novartis), against 6 haematological cell linesand 17 primary CLL cells in vitro. AUY922 induced apoptosis and amarked arrest in cell cycle progression in all the cell lines within ananomolar concentration range. In the patient samples cultured inmedia alone, AUY922 induced apoptosis irrespective of TP53 orataxia telangiectasia mutated (ATM) mutational status, of other in-dications of poor prognosis or of prior treatment. However, cultureon a CD40 ligand-expressing mouse fibroblast layer (CD40L feeder-layer) following treatment with AUY922 rescued CLL cells fromapoptosis. In contrast, pretreatment of patient cells with a combina-tion of AUY922 and fludarabine significantly decreased the numberof viable cells compared with treatment with AUY922 or fludarabinealone; an effect irrespective of poor risk features.

Culture of CLL patient cells on the CD40L feeder layer inducedan ‘activated/proliferative’ phenotype, evident as a marked increasein the expression of CD80, CD86, CD38, CD71 and CD69. Pre-treatment with AUY922 prior to culture on the CD40L feeder layersignificantly reduced the expression of all of these molecules. In con-clusion, we demonstrate that co-culture of CLL cells with a CD40Lfeeder layer confers resistance to the Hsp90 inhibitor AUY922,which can be overcome by treatment with a combination of AUY922and fludarabine. Although ineffective at overcoming the anti-apop-totic effects of the stromal layer, AUY922 as a single agent signifi-cantly reduced the CLL cell surface expression of markers of activa-tion and proliferation. As co-culture with stromal cells may modelthe tumor microenvironment our data demonstrate that combiningAUY922 with fludarabine may be an effective strategy for overcom-ing stroma-derived survival and proliferative signals.

5.43Patterns of Nodal Response and Lymphocytosisin Patients with Previously Treated CLLReceiving the Selective Phosphatidylinositol3-Kinase-Delta (PI3K�) Inhibitor, CAL-101 (GS-101) Alone or in Combination with RituximabR) or Bendamustine (B)

Jennifer R. Brown,1 Thomas M. Jahn,2 Richard R.Furman,3 John P. Leonard,3 Stephen E. Spurgeon,4

John C. Byrd,5 Don M. Benson,5 Steven E. Coutre,6

Nina D. Wagner-Johnston,7 Ian W. Flinn,8 Brad S.Kahl,9 Marshall T. Schreeder,10 Sven de Vos,11

RD(�) CR MRD(�) PR Failure

22 9 – 4

2 15 2 2

2 2 3 1

, fludarabine, cyclophosphamide, and mitoxantrone

CR M

Leanne M. Holes,2 Harriet (Sissy) Peterman,2 Dave