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ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20

Radioimmunotherapy consolidation using 131I- for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma in first remission

Mazyar Shadman, Ajay K. Gopal, Britt Kammerer, Pamela S. Becker, David G. Maloney, Barbara Pender, Andrei R. Shustov, Oliver W. Press & John M. Pagel

To cite this article: Mazyar Shadman, Ajay K. Gopal, Britt Kammerer, Pamela S. Becker, David G. Maloney, Barbara Pender, Andrei R. Shustov, Oliver W. Press & John M. Pagel (2016) Radioimmunotherapy consolidation using 131I-tositumomab for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma in first remission, Leukemia & Lymphoma, 57:3, 572-576, DOI: 10.3109/10428194.2015.1067701

To link to this article: http://dx.doi.org/10.3109/10428194.2015.1067701

View supplementary material Accepted author version posted online: 01 Jul 2015. Published online: 28 Aug 2015.

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Download by: [University of Washington Libraries] Date: 06 May 2016, At: 09:15 Leukemia & Lymphoma, March 2016; 57(3): 572–576 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1067701

ORIGINAL ARTICLE: CLINICAL Radioimmunotherapy consolidation using 131 I-tositumomab for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma in fi rst remission

Mazyar Shadman 1,2, Ajay K. Gopal 1,2 , Britt Kammerer 1 , Pamela S. Becker 2, David G. Maloney 1,2 , Barbara Pender 1, Andrei R. Shustov 2 , Oliver W. Press 1,2 & John M. Pagel 1,2

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, and 2 Department of Medicine, University of Washington, Seattle, WA, USA

Abstract eliminating MRD after initial therapy in regards to the long- Despite initial responses to chemoimmunotherapy, relapse and term outcomes of CLL patients [7 – 9]. minimal residual disease (MRD) remain major issues in treatment Radioimmunotherapy (RIT) using radiolabeled anti- of chronic lymphocytic leukemia (CLL)/small lymphocytic CD20 antibodies was introduced to potentially improve lymphoma (SLL) patients. We administered 131 I-tositumomab the effi cacy of antibody therapy for B-cell [10]. to patients in complete response (CR) or partial response (PR) Although radiolabeled antibodies have signifi cant effi cacy after induction . Toxicities and rate of PR to CR in the treatment of indolent lymphoma, their use in CLL has conversion and MRD elimination were assessed three months been limited by the extensive bone marrow involvement and later. The study stopped prematurely after enrolling 16 patients. the consequent risk of severe and prolonged myelosuppres- Four (25%) were in CR, 12 (75%) in PR, and 12 (75%) had MRD. sion. In an earlier study, RIT decreased lymphadenopathy in Three months after treatment with 131 I-tositumomab, CR was four of fi ve pretreated CLL patients but hematologic toxicity -in 12 patients and and increased infection rates were reported as major limit (%25 ;4 ؍ or sustained (n (%50 ;8 ؍ achieved (n MRD was eliminated in four of 12 patients (33%). Hematologic ing factors [11]. In a phase-II study, Jain et al . explored the toxicities were anemia in one patient (6%), in 13 use of RIT with 90Y- for treatment of (81%), and thrombocytopenia in eight (50%). Two patients CLL in the consolidation setting in 14 heavily pre-treated (12%) developed MDS 17 and 20 months after consolidation. CLL patients [12]. Clinical outcomes were not promising Consolidation with 131 I-tositumomab for CLL/SLL patients in fi rst given the low response rate (7%) and high-rate of hemato- remission is feasible and may provide the benefi t of converting logic toxicity (92%). Lack of success in that study was thought PR to CR and/or eliminating MRD. to be, at in least in part, secondary to inclusion of patients with refractory diseases who had previously failed multiple Keywords: CLL , consolidation , 131 I-tositumomab , minimal residual lines of treatment. Accordingly, in this study we investigated disease, radioimmunotherapy , SLL the tolerability and effi cacy of standard non-myeloablative 131 Downloaded by [University of Washington Libraries] at 09:15 06 May 2016 doses of I-tositumomab following primary induction che- motherapy in CLL and small lymphocytic lymphoma (SLL) Introduction patients in fi rst remission, with the goal of increasing the CR rate and minimizing the MRD burden. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries [1]. Chemotherapeu- Patients and methods tic regimens such as fl udarabine and with (FCR) or without (FR) cyclophosphamide and the combination of Eligibility bendamustine with rituximab (BR) have shown consider- Patients with CD20-positive, CLL/SLL were eligible if they able activity in patients with untreated CLL [2– 4]. Although were over the age of 18 years and if they had received most patients achieve a response, the vast majority of these prior therapy and were in fi rst remission with a partial patients will experience relapse and most patients will have (PR) or complete response (CR) to treatment at the time of minimal residual disease (MRD) after initial therapy [5,6]. enrollment. Prior to the fi rst treatment, patients with CLL A growing body of literature has suggested the importance of must have had either Rai stage III/IV disease or Rai stage

Correspondence: John Pagel, MD, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D3-190, Seattle, WA 98109-1024, USA. E-mail: [email protected] Received 20 May 2015 ; revised 16 June 2015 ; accepted 23 June 2015 572 RIT consolidation for CLL/SLL 573

I/II with evidence of disease activity as defi ned by the NCI Statistical considerations 1996 guidelines [13] and patients with SLL must have been Th is study was planned to enroll 30 patients and to proceed Stage III or IV per Ann Arbor staging system. Patients were to a larger phase II trial if the observed 2-year progression- included if they had no more than 25% intra-trabecular free survival (PFS) among the patients who received 131 I- marrow space involved by disease in a bone marrow biopsy tositumomab was 70% or higher. However, the study stopped done within 30 days of receiving the radiolabeled antibody. after enrolling 16 patients because of slow accrual as well Patients also required to have a granulocyte count Ն 1500/µ l, as manufacturer’ s decision to stop production of the drug. platelet count Ն 100 000/µ l, serum creatinine Ͻ 2 times Mann-Whitney – Wilcoxon was used to compare the ritux- upper limit of normal (ULN), total bilirubin Ͻ 2 times ULN imab level medians between diff erent treatment response and AST Ͻ 5 times ULN within 14 days of planned dosimet- groups. ric infusion. Patients with prior radiolabeled antibody treat- ment, with active brain or leptomeningeal involvement or Results with active renal or cardiac failure were excluded. Patients were also excluded if they had prior malignancies (except Between 2008 and 2012, 16 patients (CLL ϭ 11, SLL ϭ 5 ) for non- skin cancers or in situ cervical cancer) received consolidative 131 I-tositumomab in fi rst CR or PR. Th e unless they were disease-free for 5 years. All patients signed patients’ baseline characteristics are summarized in Table I. a written informed consent in accordance with institutional Th e median age was 61 (range 38 –78). Seven patients (44%) and federal guidelines. had high-risk disease based on cytogenetics or molecular profi le. Two patients (13%) had 11q22 deletion and one had Treatment protocol mutated TP53 (6%). Increased CD38 ( Ͼ 30%) and ZAP-70 Between 90 and 180 days after achieving a CR or PR, 131I- (Ͼ 20%) expression were present in three of 11 and six of tositumomab was administered in two discrete steps. First, seven patients who were tested, respectively, and unmutated a dosimetric dose of 131I-tositumomab was given on day 0 IgVH was detected in one of three tested patients. At the time and consisted of a 1-h infusion of 450 mg of unlabeled tosi- of consolidation, four (25%) patients were in CR and 12 (75%) tumomab followed by a 20-min infusion of 5 mCi (35 mg) of were in a PR after their upfront chemoimmunotherapy regi- 131I-tositumomab. Total-body gamma counts using a gamma men. Th ere was evidence of MRD at the time of consolidation camera were obtained on three occasions over the next week in 12 patients (75%) assessed by MFC. Median time interval (day 0; day 2, 3, or 4; and on day 6 or 7). Using these counts, from day 1 of their last chemotherapy to 131 I-tositumomab calculations based on standard internal radiation dosim- consolidation was 15.4 weeks and ranged from 10 –29 weeks. etry methods were performed to determine the patient- Dose reduction was needed in seven patients (44%) based on specifi c activity (in millicuries) of radiolabeled tositumomab cytopenia (n ϭ 4) or pre-treatment weight ( n ϭ 3). required to deliver a maximum tolerated therapeutic dose Th ree months after consolidation with 131 I-tositumomab, of 75 cGy total-body dose (65 cGy in patients with a plate- 12 patients were in CR (80%). Th is included four patients let count Ն 100 000 and Ͻ 150 000 cells/mm3 ). For patients (33%) who sustained the CR in addition to eight patients weighing more than 137% of their lean body weight the cal- (66%) who were in PR at the time of consolidation but culations to determine the 131 I-tositumomab antibody activ- achieved CR after consolidation. Other outcomes consisted ity were performed using an upper limit of mass (maximum eff ective mass) based upon height and gender. Second, the Table I. Patient characteristics (n ϭ 16). therapeutic dose was administered between day 7 and day Mean age, years (range) 61 (38 –78) 14. A 450 mg unlabeled tositumomab dose was adminis- Female sex, n (%) 5 (31%) tered, followed by the patient-specifi c (in millicuries) activity Diagnosis, n (%) CLL 11 (69%) Downloaded by [University of Washington Libraries] at 09:15 06 May 2016 labeled to 35 mg of tositumomab. Th yroid protective agents SLL 5 (31%) were initiated at least 24 h prior to administration of the 131I- Cytogenetics/Molecular characteristics, n (%) tositumomab dosimetric dose and continued until 2 weeks del 11 q22 2 (12.5%) TP53 mutation 1 (6.25%) after administration of the therapeutic dose. High CD38 expression (Ͼ 30%) 3 of 11 (27.2%) High ZAP-70 (Ͼ 20%) 6 of 7 (85.7%) Assessment of clinical responses Unmutated IgVH 1 of 3 (33.3%) Prior chemotherapy, n (%) Th ree months after the treatment dose, effi cacy and response FR 9 (62.5%) were recorded per NCI working group guidelines [13] and FCR 4 (25%) toxicity assessments were recorded based on the CTCAEv3.0. BR 2 (12.5%) R-CHOP 1 (6.2%) MRD was assessed by eight-color fl ow cytometry with a Disease status before 131 I-tositumomab, n (%) detection limit of 10 -3 to 10-4 on bone marrow samples to CR 4 (25%) detect CLL/SLL cells [14]. Any level of residual disease by fl ow PR 12 (75%) MRD status before 131 I-tositumomab, n (%) cytometry or cytogenetis (CG) was considered MRD positive Positive 12 (75%) and negativity of both test was required to classify a patient Negative 4 (25%) as MRD negative. Rituximab levels were determined using a Time from the fi rst day of the last treatment weeks, (range) 15.4 (10 – 29) standard ELISA method with a monoclonal anti-rituximab 131 FR, fl udarabine, rituximab; FCR, fl udarabine, cyclophosphamide, rituximab; BR, idiotype antibody before administration of I-tositumomab bendamustine, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, as previously described [15]. vincristine, prednisone. 574 M. Shadman et al.

of PR in one patient, nodular PR in one patient and disease penia in 13 (81%), and grade 3 or 4 thrombocytopenia in eight progression in one patient. One patient was lost to the fol- (50%). One patient (6%) had evidence of hypogammaglobu- low-up. Among patients who were in PR after consolidation, linemia (IgG Ͻ 400 mg/dl) 3 months after the consolidation. there was improvement in lymphadenopathy in fi ve of six of Six patients (37%) required blood or platelet transfusions. patients with measureable disease prior to 131 I-tositumomab. Two patients (12%) needed myeloid growth factor sup- Likewise, 131I-tositumomab eliminated MRD in four of port. One patient was hospitalized within 3 months of RIT 12 patients (33%) with a negative CG or MFC assay at for neutropenia-related /typhlitis. Secondary malig- 3 months (Figure 1). nancies were observed in fi ve patients (31%) and included Overall, the median pre-consolidation rituximab level myelodysplastic syndrome (MDS) (n ϭ 2; 12%), basal cell was 6.9 µ g/ml (range 0.3– 30.6). Patients with CR at 3 months carcinoma (n ϭ 2; 12%) and squamous cell carcinoma of skin had signifi cantly higher median levels of pre-treatment (n ϭ 1; 6%). MDS was diagnosed in the two patients 17 and rituximab levels (11.0 vs. 2.32 µ g/ml; p ϭ 0.02). Patients 20 months after RIT, respectively. Th ese two patients received who were in PR before consolidation and achieved CR after FR (six cycles) and FCR (six cycles) before the consolidative 131 I-tositumomab had higher median rituximab levels com- RIT, respectively, yet none of these patients received any pared to the ones who did not achieve CR (11.7 vs. 2.3 µ g/ other cytotoxic chemotherapy other than the fl udarabine- ml; p ϭ 0.04). However, there was no diff erence between based treatment and RIT before the MDS diagnosis and none the pre-consolidation rituximab levels of patients who had any evidence of dysplasia at the time of CLL diagnosis. were MRD positive before consolidation and became nega- At a median follow-up of 48 months, three patients (19%) tive after treatment and those who remained MRD positive died, one from complications of MDS, one from multi-organ (8.2 vs. 7.2 µg/ml; p ϭ 0.8). failure secondary to disease progression and one from sepsis Hematologic toxicities over the fi rst 3 months post therapy while in remission. Seven patients (44%) had relapse during were grade 3 anemia in one patient (6%), grade 3 or 4 neutro- the follow-up. Th e median duration of overall survival was not reached and the median PFS was 42 months (Figure 2).

Discussion

Th e current standard of care for front-line treatment of CLL/ SLL employs use of cytotoxic chemotherapy with fl udarabine- based regimens being the most commonly used treatments in this setting [16]. While the majority of patients achieve an initial CR or PR, the presence of MRD after treatment and later relapses remain major issues [5,6]. Assessment of MRD status after CLL treatment and its association with clinical outcomes have been an active area of investigation [7,9,17]. For example, the importance of a negative MRD status upon completion of the initial chemotherapy for CLL was recently demonstrated by Strati et al. in 237 patients [8]. In their study, the negative MRD status was found to be independently asso- ciated with improvements in both PFS and overall survival. Interestingly, the MRD negative status was associated with a better PFS regardless of the number of treatments delivered.

Downloaded by [University of Washington Libraries] at 09:15 06 May 2016 Th e authors concluded that early MRD eradication may be a reasonable goal of treatment for CLL patients and may even prompt treatment discontinuation. Implementation of novel therapeutic approaches in order to consolidate the response and to increase the number of patients with MRD nega- tive status after the initial treatment may therefore improve clinical outcomes [8]. In the current study, we demonstrated the feasibility of RIT using 131 I-tositumomab for consolidation after fi rst-line chemotherapy for CLL/SLL patients and observed that this approach may be eff ective in eliminating MRD using an eight-color fl ow cytometry developed by the University of Washington (UW)/Fred Hutchinson Cancer Research Cen- ter (FHCRC) [14]. RIT consolidation improved the complete Figure 1. Clinical response to radioimmunotherapy (RIT). Comparing clinical response rate from 25 –80% and eliminated MRD the frequency of CR and PR (panel A) and MRD negativity (panel B) in a third of patients who had evidence of CLL detected by before (left bar) and after (right bar) treatment with 131 I-tositumomab. CR, complete response; PR, partial response; nPR, nodular partial MFC or CG at the end of initial chemotherapy. Although response. * One patient was lost to follow-up. not investigated adequately in CLL to date, several clinical RIT consolidation for CLL/SLL 575

studies have shown the promise of radiolabeled antibodies ment was selected as the inclusion criteria for both studies, for treatment of indolent non-Hodgkin lymphoma (NHL). higher rates of hematopoietic toxicities in CLL patients may For example, conversion of PR to CR and prolonged relapse- at least in part be attributed to the marrow involvement free survival was reported with RIT after induction therapy for in these patients. Th ird, CD20 blockage as a result of prior advanced stage [18]. RIT had previously rituximab treatment and subsequent non-specifi c marrow been studied in the MRD setting in SLL patients. Kaminski toxicity from the unbound circulating radioisotope may also et al. reported the outcomes of SLL patients who had been explain the marrow toxicity to some degree. enrolled in four diff erent clinical trials of 131 I-tositumomab In our study, two patients (12%) were diagnosed with for NHL [19]. A total of 64% (nine of 14) of patients showed a therapy-related MDS/AML (t-MDS) approximately 1.5 years clinical response (PR conversion to CR) and severe neutro- after completion of treatment. Development of t-MDS has penia and severe thrombocytopenia were observed in 14% been a potential long-term adverse eff ect of RIT. In one and 7% of patients, respectively. In the allogeneic transplant report, 19 of 746 patients (2.5%) who received RIT with 90Y- setting, our group has previously reported an improved pro- ibritumomab tiuxetan for treatment of NHL were diagnosed gression-free survival for patients with persistent CLL/SLL with t-MDS or acute myeloid leukemia (AML) at a median of and other indolent non-Hodgkin lymphomas when 90 Y-ibri- 1.9 years (range 0.4– 6.3) after treatment with RIT [21]. Also, tumomab tiuxetan was administered before conditioning Bennett et al. followed 985 patients after treatment with 131I- regimen (fl udarabine and low dose total-body irradiation) tositumomab for NHL and reported a confi rmed diagnosis [20]. In a phase-II study from the M.D. Anderson Cancer of t-MDS/AML in 23 patients (2.3%). All those patients had Center, Jain et al. investigated the eff ect of consolidation previously received other cytotoxic treatments and in fact no with 90 Y-ibritumomab tiuxetan in 14 previously treated CLL t-MDS/AML was reported in patients who received RIT as patients who were in CR or PR [12]. While conversion of PR the initial treatment [22]. Secondary myeloid malignancies to CR was reported in one patient, there was still evidence of have also been reported after FCR-based treatments. Benja- MRD at the time of follow-up. Furthermore, most of patients mini et al . followed 234 patients after treatment with FCR- (92%) developed grade 3 or 4 bone marrow toxicity in form of based treatments for CLL and reported a t-MDS/AML rate of cytopenias. Overall, it was concluded that the rate of hema- 5.1%. Th e median time to development of secondary myeloid tologic toxicity was likely unacceptable in relapsed patients. malignancy was 2.7 years (range 1.1 –7.8) in their cohort [23]. It may, however, be argued that the observed profound bone Realizing the small sample size in our study, the shorter time marrow toxicity in that study compared to studies that used interval between the treatment and development of myeloid RIT for treatment of relapsed NHL patients could be attrib- malignancy in two patients appears to be related the prior uted to three factors. First, the CLL patients in the MD Ander- fl udarabine exposure in combination with RIT. son study were heavily pretreated with a median of fi ve treat- We examined the correlation between pre-consolidation ments prior to consolidation with RIT. In our study, patients plasma rituximab levels and the clinical outcomes. Patients had only received one line of cytotoxic chemotherapy before with a PR to the initial treatment who achieved a CR after consolidation with 131 I-tositumomab, which may explain consolidation with 131 I-tositumomab had a median ritux- the slightly lower rate of hematologic toxicity at 3 months. imab level of 11.7 µ g/ml that was signifi cantly higher than In our study, the hematologic toxicity profi le was largely as the corresponding level of 2.3 µ g/ml in patients who did anticipated at 3 months with neutropenia being the major not achieve CR after consolidation (p ϭ 0.04). Th e results cytopenia aff ecting 81% of the patients. Second, in contrast should be interpreted with caution considering the small to the other types of NHL, the majority of CLL patients had sample size. However, given the known dose-eff ect relation- a higher degree of bone morrow involvement, which is a ship between rituximab and clinical outcomes in CLL, it is known risk factor for hematologic toxicities in NHL patients possible that an ongoing eff ect of rituximab in patients with

Downloaded by [University of Washington Libraries] at 09:15 06 May 2016 undergoing RIT. Although a cut-off of 25% marrow involve- higher plasma levels augmented the response to RIT and led

Figure 2. Progression-free (panel A) and overall (panel B) survival of all patients (n ϭ 16). At the time of analysis, the median duration of progression- free survival (PFS) was 40 months and median duration of the overall survival (OS) had not been reached. 576 M. Shadman et al.

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