Allogeneic hematopoietic transplantation for mantle-cell lymphoma: Molecular remissions and evidence of graft-versus-malignancy

Annals of Oncology 10: 1293-1299, 1999. © 1999 Ktuwer Academic Publishers. Printed in the Netherlands.

Rapid publication Allogeneic hematopoietic transplantation for mantle-cell lymphoma: Molecular remissions and evidence of graft- versus -malignancy

Departments of 'Blood and Marrow Transplantation, 2Laboratory Medicine, 3Lymphoma, "Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA

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Clinical Radiology, University of Texas,

seven patients by polymerase chain reaction assay (PCR) for bcl-1 or immunoglobulin gene rearrangement. All had detectBackground: The presence of a graft-vew«5-tumor effect has able disease at the time of transplant. When tested within four been well established for various hematological malignancies months post transplant, four of these patients attained molecbut not for mantle-cell lymphoma (MCL). We report prelimi- ular remission. One of the three molecular non-responders nary results suggestive of a graft-veriuj-lymphoma effect in converted to a negative PCR status seven months later and one fluctuates between positive and negative PCR fourteen such patients post allogeneic hematopoietic transplantation. Patients and methods: Sixteen patients with the diffuse type months post transplant. Overall survival (OS) and failureof MCL received allogeneic transplantation. Three had blastic from-progression (FFP) at three years were both 55% (95% features. Fifteen had an HLA-identical and one, a one HLA confidence interval (95% CI): 28%-83%). For patients with antigen mismatched sibling donor. Fifteen had stage IV disease. chemosensitive disease, FFP and OS at one year were both Eleven patients were previously treated, including one who 90% (95% CI: 71%-100%) compared with 44% (95% CI: 1%failed prior autologous transplantation. Five patients were 88%) (P - 0.04) for those who were refractory to conventional newly diagnosed and received transplantation after cytoreduc- chemotherapy at the time of transplantation. There were six tion with three to eight courses of H YPER-CVAD (fractionated deaths. These were related to GVHD (three cases), infection cyclophosphamide, doxorubicin, vincristine, dexamethasone) (one case), multiorgan failure (one case), and graft failure (one case). alternating with high-dose methotrexate and cytarabine. Conclusions: This report demonstrates the potential effiResults: Eleven patients received high-dose cyclophosphamide 120 mg/kg and total body irradiation (TBI) (12 Gy given cacy of allogeneic hematopoietic transplantation for MCL and in four daily fractions). Three patients were not eligible for TBI provides the first evidence suggestive of graft-versus-vnsdigand received the BEAM regimen. Twelve (85.7%) achieved nancy in MCL. Data supportive of this concept include 1) complete and two (14.3%) partial response. Two additional achievement of remission concomitant with GVHD, 2) the patients received a nonablative preparative regimen consisting conversion from a positive PCR status early after transplant of cisplatin, cytarabine and fludarabine. One failed to engraft to negative PCR status over time and 3) that the only relapse and later relapsed. The other patient had progressive disease was in a patient who failed to engraft. one month post transplant but later achieved complete remission now durable for 14+ months after developing graft- versushost disease (GVHD). Residual lymphoma was assessed in Key words: allogeneic transplantation for mantle-cell lymphoma Summary

Introduction The diffuse variant of mantle cell lymphoma (MCL) is consistently associated with a poor prognosis [1-4]. With conventional chemotherapy, several reports have demonstrated a median freedom from progression (FFP) of 18 months and a median survival of 2-5 years [1-4]. High-dose chemotherapy and autologous marrow transplantation has suggested an improved outcome in patients transplanted in first remission [3], but is generally ineffective for those transplanted after relapse [5, 6]. In a recent study from the M.D. Anderson Cancer Center, the probability of FFP at three years was only 17% for

patients receiving autologous transplantation after chemosensitive relapse [5]. Prolonged remissions have been reported in patients with chronic lymphocytic leukemia [7], follicular [8-10] and large-cell lymphoma [11-20] who received allogeneic bone marrow or peripheral blood progenitor cells (PBPC) transplantation. Evidence supporting a graft-versuslymphoma (GVL) effect in these malignancies has been recently demonstrated by inducing remission through modulation of immunosuppressive therapy [21], donor lymphocyte infusions [22] and successful use of a nonablative preparative regimen [23]. Herein, we studied fourteen patients with MCL who

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I. F. Khouri,1 M.-S. Lee,2 J. Romaguera,3 N. Mirza,1 H. Kantarjian,4 M. Korbling,1 M. Albitar,2 S. Giralt1, B. Samuels,5 P. Anderlini,1 J. Rodriguez,3 B. von Wolff,1 J. Gajewski,1 F. Cabanillas3 & R. Champlin1

1294 received high-dose chemotherapy and allogeneic hematopoietic transplantation. We also report two patients with MCL who received a nonablative preparative regimen and allogeneic transplantation inducing one patient into a remission lasting for more than fourteen months.

Patients and methods Patient selection

Conditioning regimen and supportive care Cytoreduction was attempted pre-transplant with three to eight courses of fractionated cyclophosphamide 1800 mg/m 2 administered with doxorubicin, vincristine, and dexamethasone (HYPER-CVAD) alternating with high-dose methotrexate and cytarabine ( M T X ara-C) [5]. Patients proceeded to transplant even if they failed to respond to induction chemotherapy. Eleven patients received high dose cyclophosphamide 60 mg/kg daily for two days and fractionated total-body irradiation (TBI) 12.0 Gy over four fractions. Because of prior radiation, three patients received BEAM which consisted of carmustine 300 mg/m 2 intravenously (i.v.) day - 6 . etoposide 200 mg/m 2 i.v. twice daily days - 5 to —2, cytarabine 200 mg/m 2 i.v. twice daily days - 5 to —2, and melphalan 140 mg/m 2 i.v. day - 1 . Day 0 is the day of transplantation. Because of a poorer performance status and an open perirectal fistula respectively, two other patients received a nonablative preparative regimen (PFA) consisting of cisplatin of 100 mg/m 2 i.v. by continuous infusion days - 6 to - 3 . fludarabine 30 mg/m 2 daily days - 4 . - 3 and cytarabine 500-1000 mg/m 2 daily days - 4 . - 3 [23]. The patient with open fistula was refractory to prior therapy with three courses of CHOP (cyclophosphamide, adriamycin, oncovin, prednisone) and two courses of HYPER-CVAD. Five patients received marrow which was harvested and processed for ABO-incompatibility by standard measures as indicated. Allogeneic PBPC were collected from filgrastim-mobilized donors by apheresis and cryopreserved as previously reported [24]. All patients received filgrastim 5 mcg/kg/day subcutaneously starting day 1 after transplantation until recovery1 of a granulocyte count > 1.0 x 10 '/I. Graft-verjMj-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate [25] in 14 patients and tacrolimus and methvlprednisolone in one patient. One patient had a T-cell depleted transplant performed at another center. Other details of supportive care measures, including prophylactic antibiotics and transfusion policies, have been previously published [24].

Response to therapy was evaluated at months 1, 3, 6 and every six months thereafter with additional assessment as clinically indicated. Evaluation consisted of physical examination, complete blood counts, serum chemistry panel, bone marrow aspiration and biopsy, chest radiography, computed tomography of the abdomen and pelvis. Complete response (CR) was defined as the disappearance of all clinical evidence of lymphoma for a minimum of four weeks with no symptoms related to the disease. When feasible, biopsy of any residual mass was performed. Small residual masses were required to be unchanged for six months or longer off treatment to be considered a CR. Partial response (PR) was defined as greater than 50% decrease in the sum of the products of the diameters of all measured lesions for at least four weeks and nonmeasurable lesions had to decrease by at least 50%. No lesions could increase in size and no lesion could appear. Progressive disease was defined as any increase of greater than 25% in the sum of the diameters of any measurable lesions or the appearance of a new lesion. Chemosensitive disease was defined as attaining at least PR with therapy and chemoresistance was defined as stable disease or achieving less than PR. Hematopoietic chimerism was evaluated by restriction fragment length polymorphisms at the AY-29 or YNH24 loci as previously described [26]. Early preparative regimen-related toxicity was graded according to established criteria [27] GVHD was graded according to the consensus criteria [28].

Minimal residual disease The t(ll;14)(ql3;32) involving reciprocal translocation of bcl-] and JH is frequently observed in mantle-cell lymphoma. Approximately 35% — 55% of patients have the breakpoints clustered within a short DNA fragment on chromosome Ilql3, known as the major translocation cluster (MTC) region [29, 30]. The breakpoint clustering permits the use of two universal primers, one derived from the MTC region and the other from the JH region, to amplify the crossover site of the t(ll;14) [31]. Due to its simplicity in the use of two universal primers, PCR amplification of the MTC-JH region was our front line approach to assess and monitor minimal residual disease in mantlecell lymphoma. For cases not amplified by MTC-JH PCR, residual disease was analyzed by PCR for immunoglobulin gene rearrangement using the patients' lymphoma cell specific third-complementary-determining region (CDR III).

PCR amplification of the t(ll;14) at the MTC region PCR was performed using primers MTC(+) 5'-GGAGGACTTGTGGGTTGCT-3' and JH(-) 5'-ACCTGAGGAGACGGTGACC-3', followed by size-fractionation in a 3% NuSieve Gel electrophoresis and Southern transfer to a nylon membrane. The membrane was then hybridized with a biotinylated oligonucleotide probe derived from the MTC region: S'-GGTTAGACTGTGATTAGCO1. After stringent wash, the specific hybridization signal was acquired and enhanced using a chemiluminescence kit (Boehringer Mannheim, Indianapolis. IN). To ensure that optimal PCR efficiency was achieved, a reference gene, prostate-specific antigen, was coamplified in each reaction. Moreover, a weak positive control in 1:104 dilution was amplified parallel to the tested samples. To ensure that no contamination had occurred, a negative control DNA and a reagent control were also examined simultaneously.

Identification of patients' lymphoma cell-specific CDR HI sequences The pretreatment DNA samples (1 meg) were subjected to PCR amplification using a forward primer. VH(+) 5'-ACACGGCCGTGTATTACTG-3' derived from the consensus sequences at the 3' end of the VH region [32], and a reverse primer J H ( - ) (as described above). The PCR amplicons were then size-fractionated b> electrophoresis in a

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Patients with MCL were eligible to receive high dose chemotherapy if they had age < 60 years, an adequate performance status (Zubrod < 2) and no severe concomitant medical or psychiatric illnesses. Patients were required to have an HLA-identical or an one-antigen mismatched sibling donor. Patients with any of the following were ineligible: active central nervous system involvement, HIV or HTLV-1 seropositivity, bilirubin level greater than 1.5 mg/dl, cardiac ejection fraction less than 50%, or pulmonary function test and diffusing lung capacity less than 50% of predicted levels. Patients with co-morbid illnesses or poorer performance status were considered to receive nonablative preparative regimen. Informed consent was obtained from all patients, and the treatment protocols were approved by the Institutional Review Board of the University of Texas M.D. Anderson Cancer Center. The diagnosis was histologically confirmed in all cases. Disease stage was evaluated in accordance with conventional Ann Arbor criteria. Patients underwent the following staging procedures: physical examination, complete blood count with differential, serum chemistry panel, chest radiography, computed tomography of the abdomen and the pelvis, and bilateral bone marrow aspirates and biopsies.

Response criteria

1295 Table I. Patient characteristics. 16 52 30-60 10 3 5 7 1 3 3.1 1.5-6.5 495 358-1321 1 5 11 14 2

3% NuSieve Gel In case of monoclonal JH rearrangements, the PCR amphcons frequently yielded visible distinct bands that were then sliced and eluded from the gel using Qiaex gel extraction protocol as recommended by the manufacturer (Qiagen Inc., Chatsworth. CA). The purified DNA fragments were then subjected to fluorescencelabeled cycle sequencing in an ABI automated DNA Analyzer 310 (Perkin-Elmer Applied Biosystems, Foster City, CA) in both forward and reverse directions using VH(+) and J H ( - ) primers, respectively. Aligned with the germline sequence of the immunoglobulin heavy chain gene, patient-specific CDR III sequences were thereby identified and used to design the forward primer for allele-specific CDRII1 PCR in the posttreatment samples. The patient-specific forward primer, — 20 bases, spanned from the 3' end of the D region to the 3' end of the N-segment that was immediately adjacent to the 5' end of the J region.

Assessment of post-treatment minimal residual disease by allele-specific CDRIII PCR Using the patient-specific forward primer and the consensus JH(-) primer, for each patient, PCR amplifications of the posttreatment samples were performed along with a negative DNA control, a reagent control, and the patient's pretreatment sample that was serially diluted with a negative DNA in 1:10, 1:102, 1: 1.03, I : 104, 1:105, respectively. The PCR amplicons were then size-fractionated, followed by transfer onto a nylon membrane. A biotinylated ohgonucleotide probe, 5'-TTGACTACTGGGGCCAAGGAACC-3' derived from the midportion of the J segments of the JH region [33], was then used to detect the specific hybridization signal by chemiluminescence as described above. Compared with the signals of the serially diluted pretreatment samples, the positive signals detected in the posttreatment samples were graded.

Statistical methods Overall survival (OS) and FFP of all patients was measured from the date of transplantation. FFP was measured until death or progressive disease. Survival function was estimated by the Kaplan-Meier method [34], and comparisons were made using log-rank test. All P values are two-sided, and a P value < 0.05 was considered significant.

Patients Characteristics of the 16 patients are shown in Table 1. One patient had relapsed after autologous hematopoietic transplantation. All had the diffuse type of MCL. Fourteen patients had bone marrow and 10 had ^ 1 extra nodal site involvement. Fifteen had stage IV and one stage III disease. Five were in first remission; three of these patients had blastic features. Seven other patients failed to respond to prior chemotherapy with CHOP given at other institutions. Three of these patients later achieved PR to salvage therapy with HYPER-CVAD/ MTX-ara-C prior to transplant. One patient was in refractory and three were in chemotherapy sensitive relapse. The median interval between diagnosis and transplantation was 13 months (range 3-48 months). Fifteen had HLA-identical and one had an one-antigen mismatched sibling donors. Response Of the 14 patients receiving high-dose cyclophosphamide/TBI or BEAM therapy, 12 (85.7%) were in CR and 2 (14.3%) PR. Two patients received the PFA nonablative preparative regimen. One of the two had blastic features and was in first remission (PR) at the time of transplant. He received the lower dose level of the PFA regimen and failed to engraft. He subsequently rejected a second transplant from the same donor using BEAM as the preparative regimen and later died of progressive disease. The other patient was refractory to three prior chemotherapy regimens including the HYPER-CVAD/ MTX-ara-C. He had an open perirectal fistula that had previously caused sepsis. He received the higher dose level of PFA and engrafted. His marrow analysis showed 85% lymphoma cells at one month post transplant. He developed acute GVHD involving the gastrointestinal tract on day 84 and later progressed to cutaneous and gastrointestinal chronic GVHD that responded to immunosuppressive therapy with methylprednisolone. Concomitant with this process, the lymphoma regressed. His marrow analysis at 14 months showed CR, with negative studies for minimal residual disease by flow cytometry (Table 2). FFP and survival

Nine patients remain alive. Eight are in CR. One is in PR, three months post transplant. One patient who failed engraftment had progressive disease. No other patient has relapsed. The median follow-up time for the surviving patients is 24 months (range 3-40 months). Both FFP and overall survival (OS) rate at three years for all patients were 55% (95% confidence interval (95% CI): 28%-83%) (Figure 1). There was a significant difference in FFP and OS when patients with sensitive versus refractory disease at

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Number of patients Age (years) Median Range Patient sex Male Female Disease status First remission Induction failure Refractory relapse Sensitive relapse B2M (mg/1) Median Range LDH (IU/1) Median Range Prior transplantation Stem-cell source Marrow Peripheral blood Preparative regimen Ablative Nonablative

Results

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marrow graft and development of a graft-versus-malignancy effect. Lower dose relatively nontoxic preparative regimens may produce less morbidity and can be effective in diseases in which potent graft-versw.s-malignancy effects are operative. We [23, 39, 40] and others [41, 42] have evaluated this strategy by using sublethal doses of chemotherapy and/or radiation as the preparative regimen. Two patients in our study underwent such a strategy. The ability to achieve remission in one patient who had serious co-morbid medical problems at the time of transplant is a proof of principle of this strategy and this approach requires further study in this disease, in which the median age is > 60 years. Given the encouraging results with established high-dose therapy, we recommend study of nonablative regimens only in patients not eligible for high-dose therapy because of older age or comorbidities. These data suggest that GVL is operative in MCL and that allogeneic transplantation is a potentially effective therapy for this disease. Treatment of larger numbers of patients with long-term follow-up is necessary to define the role of allogeneic hematopoietic transplants versus other treatment modalities.

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Correspondence to: I. F. Khoun, MD University of Texas, M.D. Anderson Cancer Center Department of Blood and Marrow Transplantation 1515 Holcombe Blvd., Box 65 Houston, TX 77030 USA E-mail, [email protected]

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