and Autologous Stem Cell Transplantation for
Peter R. Holman,1,
Edward D. Ball1
The treatment of low- and intermediate-grade subtypes of malignant lymphoma continues to evolve. Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma (NHL) and is generally considered incurable. Although high response rates can be achieved with initial chemotherapy, median survival is only 3-4 years. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been reported to improve progression-free survival (PFS), but most patients eventually relapse. Indolent lymphoma accounts for 35% of all NHL and is associated with a median survival of 9 years. Similar to MCL, it is also generally considered incurable, and the PFS also appears to be improved following HDT/ASCT. We initiated a pilot study to evaluate idiotype (Id) vaccination following HDT and ASCT for patients with MCL, indolent, and transformed NHL to evaluate the ability of Id-keyhole limpet hemocyanin (KLH) to in-duce immune responses, and to evaluate overall survival (OS) and PFS. We treated 15 patients: 8 with MCL, 4 with follicular lymphoma, 1 with small lymphocytic lymphoma, and 2 with transformed lymphoma. After a median follow-up of approximately 6.3 years (range: 1-9), PFS and OS at 9.05 years from time of ASCT are 59% and 52%, respectively.
Biol Blood Marrow Transplant 18: 257-264 (2012)Ó 2012 American Society for Blood and Marrow Transplantation KEY WORDS: Non-Hodgkin lymphoma, Autologous stem cell transplantation, Idiotype vaccination, Immunotherapy
The treatment of low- and intermediate-grade subtypes of non-Hodgkin lymphomas (NHL) con-tinues to evolve. The introduction of immunothera-peutic strategies has become an attractive means of treatment, particularly with the use of passive immu-notherapy (eg, rituximab). High response rates can be achieved with chemotherapy, monoclonal anti-bodies, and radioimmunotherapy. However, progres-sion of disease is frequent. Intensified consolidation with high-dose therapy (HDT) and autologous stem
cell transplantation (ASCT) has been reported to improve progression-free survival (PFS), but most patients ultimately relapse[1-4].
The use of idiotype (Id) immunization to develop an anti-Id antibody immune response has been dem-onstrated as a promising approach to the treatment of B cell lymphomas, and could result in more durable remissions and improved overall survival (OS) than with standard chemoimmunotherapeutic options[5-7]. Immunoglobulin (Ig) molecules on the surface of clonal B cells in NHL can be used as a tumor-specific target for immunotherapy. A unique Ig receptor ex-pressed on the malignant B cell surface contains a specific antigen-recognition region, the Id, which can be targeted as a strong antigen for the induction of an anti-Id immune response. The coupling of the Id protein to keyhole limpet hemocyanin (KLH) and simultaneous local administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) produces an augmented immune response targeted at malignant B cells while sparing normal B cells [5,8]. Studies in animals and humans have shown the effectiveness of the immune system to target Id and kill lymphoma cells [9-12]. Treatment with monoclonal anti-Id antibodies can cause tumor
From the 1Moores UCSD Cancer Center, Blood and Marrow
Transplantation Division, La Jolla, California; and2University
of Iowa, Iowa City, Iowa.
Financial disclosure: See Acknowledgments on page 262. * The first 2 authors contributed equally to this article.
Correspondence and reprint requests: Edward D. Ball, MD, Moores UCSD Cancer Center, Division of Blood and Marrow Transplantation, 3855 Health Sciences Drive MC-0960, La Jolla, CA 92093 (e-mail:firstname.lastname@example.org).
Received April 19, 2011; accepted June 27, 2011
Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00
regression and possibly induce long-term clinical remissions[12,13].
Invariably, early clinical trials in patients with B cell lymphomas have shown that Id vaccination is effective in eliciting specific anti-Id responses, accom-panied by clinical benefit[14,15]. Long-term follow-up of these patients has shown improved clinical out-comes with prolonged PFS and OS. Recent trials have evaluated the use of Id vaccination in patients with follicular non-Hodgkin lymphoma (NHL[FL]). Early trials showed tumor regression and durable ob-jective responses to vaccination in pretreated patients with relapsed/refractory NHL used as a single agent, or following rituximab immunotherapy[16-19].
Prior studies have demonstrated a strong inverse correlation between the presence of detectable malig-nancy and the laboratory detection of a cellular or hu-moral Id-specific immune response [5,20]. Enhanced immune responsiveness to vaccination that was seen in patients in complete remission (CR) at the time of vaccination prompted the hypothesis that a vaccine was most effective in patients with minimal or no detectable residual disease. This suggested the consideration of HDT followed by ASCT as a means to achieve a maximal response to therapy while providing an ideal opportunity to mount an effective immune response via Id vaccination. Davis et al. demonstrated the feasibility of this concept in 12 pre-treated patients with refractory or relapsed B cell lym-phomas, producing prolonged remissions particularly in patients with FL. The applicability of Id vaccination after ASCT in other subtypes of B-cell lymphoma has not yet been evaluated.
Mantle cell lymphoma (MCL) was originally de-scribed more than 30 years ago but was finally ac-cepted as a separate entity when it became evident that the t(11;14)(q12;q32) translocation was consis-tently present [22,23]. MCL accounts for 6% of all NHL and is often indolent or moderately aggressive at diagnosis, but with time the disease invariably becomes clinically aggressive and chemotherapy refractory. It has shown the worst long-term survival among all B cell lymphoma subtypes, and is generally thought to be incurable. Although high response rates can be achieved with initial chemotherapy for MCL, median survival is only 3-4 years . Data of cohorts following HDT and ASCT suggest a higher event-free survival (EFS) and OS compared with historic controls [2,26-32]; however, no randomized trial has reached conclusive results . All data suggest that there is no disease-free plateau, and therefore relapse is likely in most patients with MCL. Data from the Nordic Lymphoma Group MCL2 study and the M. D. Anderson Cancer Center, however, have recently shown that intensified con-solidation with HDT and ASCT could provide long-term disease control in chemotherapy-na€ıve
patients in first CR [28,33]. Although recent data has been promising, relapse rates after HDT and ASCT remain high[26,28,33-36].
With this background, we initiated a pilot study evaluating Id vaccination following HDT and ASCT for patients with MCL, indolent NHL, and trans-formed NHL (TL) to explore the feasibility and effi-cacy of this post-ASCT immunotherapeutic strategy to induce and maintain complete clinical or molecular remissions.
METHODS Patient Population
Between April 2001 and September 2006, 32 pa-tients with NHL were enrolled in a pilot study to eval-uate the feasibility, safety, and potential efficacy of Id immunization following HDT and ASCT. Eligible patients were between the ages of 18 and 75, had a Karnofsky Performance Status of $70%, and had received any number of prior chemotherapy regimens. Patients may not have undergone prior HDT and ASCT. Histologic confirmation of lymphoma was re-quired and included patients with small lymphocytic lymphoma (SLL), follicular small cleaved cell, follicu-lar mixed small and follicu-large cell, MCL, or TL. Patients were required to have a left ventricular ejection frac-tion.40%, diffusion lung capacity of carbon monox-ide.40% of predicted, creatinine\1.8 mg/dL, and be a candidate for ASCT. Patients were excluded for known central nervous system lymphoma or menin-geal lymphomatosis, human immunodeficiency virus, or chronic inflammatory disorders requiring the continued use of glucocorticoids or other immunosup-pressive medications. The population included 16 pa-tients with FL, 10 with MCL, 3 with TL, 2 with SLL, and 1 with marginal zone lymphoma (MZL). The institutional review boards of the participating centers approved the study. Written informed consent was obtained from all participants before enrollment. Treatment Design
A lymph node biopsy, peripheral blood draw, or bone marrow biopsy was performed on eligible patients to provide material for the generation of tumor-specific Id. Patients whose lymphoma cells expressed surface Ig were then eligible to continue on the study. All patients had measurable disease after obtaining tissue for vaccine production. Following tissue collection, patients proceeded to undergo a standard cytoreductive chemotherapy regimen before stem cell mobilization, and HDT followed by ASCT. Cytoreductive chemotherapy was chosen and administered at the discretion of the treating physician, although fludarabine and rituximab were
discouraged because of their known effects on the cellular and humoral immune systems, respectively. Vaccination was initiated at least 3 months after trans-plantation, and followed an immunization schedule as outlined below. Patients have subsequently been fol-lowed for clinical and radiographic signs of relapse. Vaccine Production
Id was produced by a proprietary recombinant technology from the tumor-specific Ig light and heavy chain genes captured from each individual patient’s lymphoma cells, as previously described . These genes were molecularly identified by polymerase chain reaction (PCR) amplification and cloned into a dual gene baculovirus expression vector  containing IgG1 (heavy chain, Vh) and kappa or lambda (light chain, VL) constant regions. Following identification of the tumor derived Ig Vh and VL region sequences, heavy and light chain coding products were cloned, and the Ig was subsequently coupled to KLH using glutaraldehyde.
Patients received a monthly subcutaneous vaccina-tion of Id-KLH together with 250 mg GM-CSF at a minimum of 3 months following ASCT, and vaccina-tion was repeated for 4 consecutive months. This was followed by a final vaccination 2 months thereafter. A total of 250 mg GM-CSF was administered alone by daily injections for 3 days following each Id-KLH vaccination to enhance the immunogenicity and anti-tumor effects, consistent with previous studies to enhance the efficacy of the vaccine[37,39].
Cellular and Humoral Response Evaluation To evaluate the ability of Id-KLH/GM-CSF to in-duce cellular and immune responses, peripheral blood mononuclear cells were obtained and cultured with KLH, autologous Id, or a control patient Id. The blood samples were obtained before each vaccination and at 4 weeks following the completion of therapy. The frequency of CD41T cells that stain for cytoplas-mic interferon (IFN)-g or tumor necrosis factor (TNF)-a was determined. A positive T cell response to KLH was indicated by a result above the mean plus 3 standard deviations observed in the controls. A positive T cell response to Id is indicated by a result 3-fold higher than that observed with the irrelevant control Ig.
To evaluate humoral immune responses, serial di-lutions of serum samples were added to wells contain-ing Id Fab fragments, KLH-coated wells, Id-KLH, or a sham control. The presence of bound antibody was detected using a goat anti-human IgG horseradish peroxidase-conjugated antibody preparation in a stan-dard enzyme-linked immunosorbent assay. At any
point measured, a positive response to KLH was indi-cated by a result above the mean plus 3 standard devi-ations observed in the controls. A positive result to Id was indicated by a result 3-fold higher than that observed with the irrelevant control Id.
Patients underwent routine staging by clinical ex-amination, bone marrow, and peripheral blood evalu-ation, and computed tomography (CT) or magnetic resonance image (MRI) evaluation, before induction chemotherapy, before HDT/ASCT, and at 30 days following ASCT. Repeat evaluations of disease status were performed at 3, 6, 9, and 14 months post-ASCT. All patients were monitored closely for toxicity during the study period. For non-MCL patients, molecular evaluation of the bone marrow/peripheral blood using PCR for the t(14;18) were obtained pre-ASCT. No patients were found to have this chromo-somal abnormality.
The durations of PFS and OS were calculated from the date the patient underwent ASCT until the date of disease progression (PFS) and the date of death from any cause (OS), or last follow-up as appropriate. The probabilities of these outcomes as a function of time were determined by the Kaplan-Meier method.
From April 2001 to September 2006, of the 32 pa-tients enrolled in this pilot study, 15 papa-tients received Id immunization following HDT and ASCT. All patients received HDT with Carmustine, etoposide, cytarabine, and melphalan (BEAM) except for 1 MCL patient who received cyclophospohomide, etoposide, and carmustine (CEB), and 1 TL patient who received
131I-tositumomab, cytarabine, and etoposide. Of the
17 patients who came off study before receiving im-munization, 12 had FL. Of these FL patients, 3 with-drew consent, 1 underwent allogeneic stem cell transplantation, 1 had an inadequate stem cell collec-tion, and 1 was excluded for chronic steroid use result-ing from BCNU toxicity post-ASCT. Vaccines could not be produced for 6 FL patients. Of the remaining 5 patients, vaccines could not be made for 1 patient with TL, and 4 patients were ultimately not recom-mended for ASCT. Fifteen patients received Id immu-nization: 8 with MCL; 4 with FL; 1 with SLL; and 2 with TL (Table 1) The median number of prior reg-imens for all patients was 2 (range: 1-5), and all but 1 patient demonstrated chemosensitivity before ASCT. Following induction therapy, 5 patients proceeded to
HDT and ASCT in a partial remission (PR), 5 in first CR, and 4 in second CR. One patient proceeded after first relapse. For MCL patients, the median number of prior regimens was 2 (range: 1-5), including rituximab, cyclophosphamide, doxorubicin, vincristine, and pred-nisone (R-CHOP), and cyclophosphamide, vincris-tine, doxorubicin, and dexamethasone (hyperCVAD) with or without rituximab. Five of the 8 MCL patients received hyperCVAD as treatment. FL patients had previously received a variety of regimens, including: fludarabine; cyclophosphamide, vincristine, and pred-nisone (CVP); CHOP; rituximab alone or in combina-tion; and 90Y-ibritumomab. No patient received rituximab as part of a maintenance regimen, just before or after transplantation, or for the purpose of graft purging.
After ASCT and before immunization, all but 1 patient had stable disease, a PR, or a CR. Patients re-ceived the first vaccination between 3 and 7 months
post-ASCT. All but 1 patient completed the immuni-zation schedule and received all 5 vaccinations. Patient 14 received only 2 vaccines because of evidence of pro-gressive disease.
The median follow-up after ASCT and Id vaccina-tion is 6 years, ranging from 1 to 9 years. Of the 15 treated patients, 8 are alive and are in CR (Table 2). Six patients died of progressive disease, and 1 FL pa-tient died of myelodysplasia that progressed to acute myeloid leukemia (AML) at 34 months post-ASCT without evidence of lymphoma. All 8 patients with MCL achieved CR following ASCT, and 5 have re-mained in continued CR (CCR) between 76 and 108 months post-ASCT. Three patients with MCL patient relapsed at 10, 13, and 47 months after ASCT. Of the 3 FL patients who achieved CR, 2 continue in CR at
Table 1. Patient Characteristics
Patient No. Age Sex Histology
No. of Prior Regimens
Disease Response Before ASCT
Time from ASCT to Vaccination (Months) 1 63 M MCL 2 CR 6 2 61 M MCL 3 PR 3 3 56 M MCL 1 CR 6 4 62 M MCL 2 CR 4 5 60 M MCL 2 CR 3 6 52 M MCL 1 CR 4 7 66 M MCL 1 CR 3 8 50 M MCL 1 CR 7 9 54 M FL 5 PR 3 10 54 F FL 1 PR 4 11 54 F FL 3 PR 4 12 48 M FL 4 PR 3 13 51 M TL 5 PR 6 14 66 M TL 2 PR 3 15 27 M SLL 3 SD 5
ASCT indicates autologous stem cell transplant; MCL, mantle cell lymphoma; FL, follicular lymphoma; TL, transformed lymphoma; SLL, small lymphocytic lymphoma; CR, complete response; PR, partial response; SD, stable disease.
Table 2. Clinical Responses
Patient Histology Response Prevaccine 1 Response Prevaccine 4 Response at 9 Months Response at 14 Months Time Since
ASCT (Months) Status
1 MCL CR CR CR CR 108 Alive—CR
2 MCL PR CR CR PD 23 Expired—PD
3 MCL CR CR CR CR 72 Expired—PD
4 MCL CRu CRu CRu CR 94 Alive—CR
5 MCL CR CR CR CR 90 Alive—CR
6 MCL CR CR PD Off study 20 Expired—PD
7 MCL CR CR CR CR 76 Alive—CR
8 MCL CR CR CR CR 79 Alive—CR
9 FL PR CRu CR CR 34 Expired— MDS/AML
10 FL SD SD SD SD 106 Alive—CR
11 FL CR CR CR CR 80 Alive—CR
12 FL PD PD PD PD 22 Expired—PD
13 TL SD SD SD SD 91 Alive—CR
14 TL CR PD Off Study — 6 Expired—PD
15 SLL CR CR CR CR 26 Expired—PD
MCL indicates mantle cell lymphoma; FL, follicular lymphoma; TL, transformed lymphoma; SLL, small lymphocytic lymphoma; CR, complete response; CRu, complete response unconfirmed; PR, partial response; SD, stable disease; ASCT, autologous stem cell transplant; PD, progressive disease; MDS/AML, myelodysplastic syndrome with progression to acute myelogenous leukemia.
80 and 106 months post-ASCT. One patient with TL achieved a CR post-ASCT, but had progressive disease at month 45. That patient subsequently underwent al-logeneic stem cell transplantation and has remained in a CCR. With a median follow-up of 6.3 years (range: 1-9), the PFS and OS at 9.05 years from the time of ASCT are 59% and 52%, respectively (Figures 1 and 2). After a median follow-up of up to 6.3 years, PFS and OS for MCL at 9.05 years from the time of ASCT was 62.5% and 60%, respectively. No patient with MCL showed disease progression after 4 years or died after 6 years.
Id immunizations were well tolerated, with injec-tion site reacinjec-tions being the most commonly reported adverse events. Grade 3 toxicities included leucopenia in 1 patient, vitreous hemorrhage in 1 patient, liver abscess in 1 patient secondary to biliary stent obstruc-tion, infection in 1 patient, and syncope in 1 patient. As stated previously, 1 patient developed a secondary treatment-related AML. All of these toxicities were thought to be transplant-related events, not likely related to Id vaccination. No limiting, sustained, or delayed toxicities were identified, and no adjust-ments were made to the vaccine formulation because of toxicity.
Specific anti-Id and anti-KLH responses, both hu-moral and cellular, were noted in the majority of treated patients (Table 3). Anti-KLH and anti-Id hu-moral responses were noted as early as after the second vaccine, although the majority of responders were noted to be after the third vaccine. The patients who developed a cellular anti-KLH and anti-Id response did so after the second vaccine, although it was noted to have occurred after the first vaccine in 3 patients. Of the 5 patients with MCL with a CCR, 3 developed
anti-KLH and anti-Id cellular responses, 1 developed anti-Id cellular response only, and 1 was not tested. The patient with MCL who relapsed after 47 months also had both anti-Id and anti-KLH cellular responses. Three of the 4 FL patients developed anti-KLH humoral responses, and 2 developed anti-Id humoral re-sponses. Of the 3 FL patients who obtained a durable CR, 2 developed an anti-Id and anti-KLH cellular response, and the third was not tested. A lack of viable cells for uation upon shipment to a reference lab limited the eval-uation of an immune response for several patients.
This pilot study illustrates the use of Id vaccination as a feasible immunotherapeutic intervention follow-ing ASCT for NHL. Early and Id-specific immune
Figure 1. PFS of patients who received idiotype vaccination after ASCT for NHL.
Figure 2. OS of patients who received idiotype vaccination after ASCT for NHL.
Table 3. Immune Responses to Id Vaccination Post-ASCT
Cellular Responsiveness Anti-KLH Anti-Id Anti-KLH Anti-Id
1 MCL + + + + 2 MCL 2 2 2 2 3 MCL + NSR + + 4 MCL + + + + 5 MCL 2 2 + + 6 MCL + + NT NT 7 MCL + 2 NT NT 8 MCL 2 NT 2 + 9 FL + + + + 10 FL + NSR + + 11 FL + + NT NT 12 FL 2 2 NT NT 13 TL + + 2 2 14 TL NT NT NT NT 15 SLL + 2 NT NT
Id indicates idiotype; ASCT, autologous stem cell transplantation; KLH, keyhole limpet hemocyanin; MCL, mantle cell lymphoma; FL, follicular lymphoma; TL, transformed lymphoma; SLL, small lymphocytic lym-phoma; NSR, nonspecific response; NT, not tested.
responses were seen in vaccinated patients post-ASCT as treatment for both indolent and more aggressive lymphomas. Durable clinical responses were seen with this approach, even in this heavily pretreated pop-ulation. The early appearance and durability of specific immune responses may be attributable to the adminis-tration of Id immunization during a window of immune reconstitution following HDT/ASCT. Early data on tumor-specific Id vaccines for the treatment of NHL suggest that its use would be most effective in patients with minimal or no detectable residual disease. The use of HDT/ASCT provides an ideal opportunity to note effective immune responses to a vaccine based on the unique Ig protein expressed by tumor cells.
Our study confirms previous data from animal models that establish the ability of the immune system to reconstitute and mount robust immune responses as early as 2 weeks after myeloablative therapy [40,41]. T cell reconstitution may depend on the maturation of peripheral cells present in the graft during the posttransplantation setting of minimal residual disease. As demonstrated in murine studies, the maturing T cells may be antigen driven and with the added advantage of immune reconstitution posttrans-plantation, a specific window may be created for the induction of a vigorous Id-specific immune response . The use of HDT may lead to a depletion of regulatory T cells. A loss of this population of T lym-phocytes, crucial in the control of T cell-mediated autoimmunity by suppressing the proliferation and cytokine production of other T cells, could allow for an even more robust immune response.
Clinical studies of the use of Id vaccine in NHL have largely focused on its use in the pretransplantation setting in FL [8,16,19,37,43,44]. Despite early enthusiasm, 2 phase III studies showed no benefit of Id vaccine after induction chemotherapy for FL. These data have assuaged its use and halted further production of the respective vaccines [37,45]. Recent data on the use of rituximab in FL for in vivo purging and maintenance may also potentially overshadow the proposed benefit of Id vaccination . These data were not available before initiating this study, and ritux-imab was not used in these manners.
The potential benefit of Id vaccination in MCL is not well established. Early studies showed the safety and feasibility of Id vaccination following chemother-apy in patients with MCL [47,48]. Anti-Id immune responses were observed, even after rituximab-based chemotherapy, showing that severe B cell depletion does not impair T cell priming in humans . Our preliminary data showed that early development of ro-bust immune responses may translate into prolonged posttransplantation disease-free survival (DFS) in MCL.
HDT/ASCT has been shown to improve the clini-cal outcomes in MCL, a disease in which chemotherapy
alone is insufficient for cure [2,51-56]. The MCL2 Study showed encouraging results for the use of intensive immunochemotherapy followed by ASCT, with no relapses seen after 5 years. Updated data after a median follow-up of 5.6 years reported a 10-year OS of 58%; however, late relapses were seen.
Few studies have evaluated the use of Id vaccina-tion in the posttransplantavaccina-tion setting . This study provides follow-up after 9 years in patients with NHL who underwent HDT/ASCT followed by Id vaccination. The PFS and OS, 59% and 52%, respectively, suggest the possibility of long-term dis-ease control using this strategy. The 9-year PFS and OS of MCL patients, 62.5% and 60%, respectively, also support the notion of improved long-term out-comes in a lymphoma historically associated with a poor prognosis. Because late relapses are of concern after transplantation for MCL, no patient showed disease progression after 4 years or died after 6 years in this study.
Long-term follow-up of this population shows promising effects of Id vaccination in the posttrans-plantation setting on PFS and OS. Of the 15 patients treated, 8 (53%) have shown durable remissions, 5 of which were seen in patients with MCL. Detailed anal-ysis of this subset of MCL patients showed a group of male patients, age 50-66, stage IV disease, Karnofsky Performance Status .70%, and few or no medical comorbidities. Induction regimens included either hyperCVAD or CHOP, with or without rituximab. Three of these patients underwent ASCT in first CR, and 2 patients in second CR. The similarities among these long-term survivors with MCL may provide a specific subset of patients to target for successful Id vaccination in the future.
This experience supports the concept of Id vacci-nation in the post-ASCT setting as a safe, feasible, and effective intervention in patients with NHL. Our data suggests the idea that there is an immune compo-nent that can be exploited in this setting, and this strategy may extend to more aggressive lymphomas. Id vaccination in patients with MCL who undergo ASCT shows early promise of providing durable remissions and prolonged OS. Further investigation of the use of Id vaccination in the posttransplantation setting for MCL is necessary on a larger scale to con-firm these findings.
This study presents a form of immunotherapy that shows favorable effects on long-term disease control in a subset of patients with MCL. We hope that these re-sults spur a renewed interest in continuing this approach.
Financial disclosure: The authors have no conflicts of interest to disclose.
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