Nonmyeloablative Allogeneic Transplantation Research Articles

The potential benefits of participating in early-phase clinical trials in multiple myeloma: long-term remission in a patient with relapsed multiple myeloma treated with 90 cycles of lenalidomide and bortezomib

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m(2) of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM.

Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.

Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity.

Are reduced-intensity transplants safe in older patients with hematologic malignancies?

Evaluation of: Sorror ML, Sandmeier BM, Storer BE et al. Long-term outcomes among older patients following non-myeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA 306(17), 1874–1883 (2011).Non-myeloablative allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy for older patients with hematologic malignancies. However, the treatment modality is underutilized and, to date, there are only limited data on outcomes in people older than 60 years. This study describes the toxicities and outcomes of non-myeloablative allogeneic HCT, conditioned with low-dose total body irradiation with or without fludarabine, in patients aged 60–75 years enrolled in prospective multicenter clinical trials. Increasing age was not associated with adverse outcome. Relapse risk and comorbidity burden predicted survival; fit patients with low risk of disease relapse did well after transplant regardless of age. Despite demonstrating the feasibility of non-myeloablative allogeneic HCT in patients aged 60–75 years, the study raises important questions regarding how best to manage older patients with high-risk hematologic malignancies and how to optimize our approach to allogeneic HCT in this age group.

Long-term remission after nonmyeloablative allogeneic bone marrow transplantation in a relapsed Hodgkin lymphoma patient with CNS involvement

Long-term remission after nonmyeloablative allogeneic bone marrow transplantation in a relapsed Hodgkin lymphoma patient with CNS involvement

Tandem Autologous–Allogeneic Nonmyeloablative Sibling Transplantation in Relapsed Follicular Lymphoma Leads to Impressive Progression-Free Survival with Minimal Toxicity

Autologous stem cell transplantation (ASCT) prolongs survival in patients with relapsed follicular lymphoma. ASCT is usually not curative, however. Myeloablative allogeneic transplantation has produced long-term survival at a cost of significant transplantation-related mortality (TRM), whereas reduced-intensity transplantation entails less TRM but has a higher relapse rate. We thus initiated a protocol consisting of ASCT followed by nonmyeloablative allogeneic transplantation (NMT) for relapsed follicular lymphoma to mimic myeloablative allogeneic transplantation without the associated toxicity. The NMT was non-T cell-depleted, and all donors were HLA-identical siblings. We report results in 27 patients with a median age of 49 years (range, 34-65 years). Five patients demonstrated histological progression toward an aggressive lymphoma. The patients had received a median of 3 lines of previous therapy. Disease status before ASCT included 8 patients in complete remission, 14 in partial remission, and 5 refractory. Five patients developed grade II-IV acute graft-versus-host disease, and 20 patients developed chronic graft-versus-host disease requiring systemic therapy. With a median follow-up of 39 months after NMT, overall survival and progression-free survival were 96% at 3 years. We conclude that the combined ASCT-NMT strategy appears to be safe, with excellent progression-free survival even in refractory and transformed cases. This novel approach warrants further investigation in larger prospective studies.

Graft-Versus-Lymphoma Effect After Non-Myeloablative Allogeneic Transplant Induces Molecular Remission Assessed by High-Throughput Sequencing of T Cell Receptor in Patients with Advanced Stage Mycosis Fungoides and Sezary Syndrome

Abstract 3114Mycosis fungoides (MF) is a mature T-cell lymphoma arising primarily from the skin. Patients with advanced stage disease either with skin tumor lesions or its leukemic form, Sezary syndrome (SS), consistently require therapy for disease control and symptom relief. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed non-myeloablative allogeneic transplant in 11 MF/SS patients using total skin electron beam therapy (TSEBT), total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) preparative regimen in an attempt to provide prolonged disease control. The median age was 63 years (range 20–73). All but one patient had stage IV disease at the time of preparative regimen. The median number of prior systemic therapies was 5 (range 2–8). Eight patients achieved complete response after transplant and 3 patients had partial response (ORR 100%). However, 4 patients experienced disease progression post transplant, requiring additional therapy. Patients tolerated the transplant extremely well. Only one patient developed grade 2 acute GVHD (skin), and another patient developed extensive chronic GVHD (skin, oral, GI). All patients were alive at the last evaluation (median follow-up, 10.6 months).The current method for monitoring residual disease in MF/SS uses flow cytometry to detect circulating Sezary cells and pathological evaluation of skin biopsy samples. However, there are no MF/SS specific tumor markers that can easily and consistently differentiate malignant clones from normal T cells and these standard diagnostic tools lack sensitivity in detecting minimal residual disease (MRD). Here, we tested whether high-throughput sequencing of T cell receptor (TCR) provides a new tool for monitoring MRD after allogeneic transplant. Genomic DNA was extracted from either peripheral blood mononuclear cells or selected skin biopsy samples. The rearranged VDJ of TCR ß was amplified using V ß-specific forward and J ß-specific reverse primers. The Illumina GA2 system generated up to 1, 000, 000 reads of 54 base pairs, covering the entire CDR3 lengths. Raw sequence data were processed to remove PCR/sequencing errors, and a nearest neighbor algorithm was used to collapse the data into unique sequences (Blood 2009, 114 :4099). Of blood samples from six SS patients, malignant clone was identified in all 6 cases by a dominant unique TCR ß CDR3 sequence. At the time of preparative regimen, 3 patients had measurable circulating Sezary cells by standard flow cytometry and pathological evaluation of peripheral blood smear. TCR ß sequencing data showed that malignant clones contributed to 69%, 81% and 68% of circulating T cells in these 3 patients, respectively. The other 3 patients did not have detectable circulating Sezary cells by standard diagnostic tools. However, 8.47%, 0.38% and 0.22% of the TCR ß sequences were from the malignant clones in these 3 cases at the time of preparative regimen. The percentage of malignant T cell clones decreased in all cases immediately after transplant. Three patients eventually achieved molecular remission. Two of them cleared the malignant clone at day+30 and the third cleared the MRD at day+270. The follow-up is still short to determine whether achieving molecular remission correlate with better clinical outcome. We have also started to perform TCR ß sequencing of skin biopsy samples to assess the MRD status in the skin of MF patients. In addition to providing highly sensitive and specific MRD quantification, deep sequencing of TCR also revealed vital information on the T cell repertoire reconstitution after allogeneic transplant. Based on our preliminary data, adaptive transfer of donor TCR repertoire clearly occurred immediately after allogeneic transplant and the TCR diversification slowly appeared months later.In summary, we have shown a safe and effective unique preparatory regimen for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. We also demonstrated the utility of high throughput sequencing of CDR3 of TCR ß in assessing MRD status after therapy with utmost sensitivity and specificity, and for the first time, showed a therapy resulting in molecular remission in this patient population. Disclosures:No relevant conflicts of interest to declare.

Nonmyeloablative Allogeneic Stem Cell Transplantation with/ or without 90yttrium Ibritumomab Tiuxetan (90YIT) Is Curative for Relapsed Follicular Lymphoma: Median 9 Year Follow-up Results

Abstract 662 Purpose:Fludarabine, cyclophosphamide, and rituximab (FCR) has been found to be an effective nonmyeloablative allogeneic conditioning for relapsed/chemosensitive follicular lymphoma (Khouri et al, Blood 2008;111:5530). Innovative strategies were needed to treat patients with refractory disease. To achieve this goal, we added in a subsequent trial 90YIT to the conditioning (90YIT-FC). We now report updated results of the FCR trial (n=47 pts), and outcomes after 90YIT-FC (n=26 pts). Methods: FCR regimen: Fludarabine (30mg/m2) and cyclophosphamide(750mg/m2) were each given daily for 3 days (-5 to −3) before transplantation. Rituximab was given at a dose of 375 mg/m2 on day –13 and 1000 mg/m2 on days −6, +1, and +8, as previously described. 90YIT-FC: A diagnostic dose of 111In-ibritumomab was administered on day-14, followed by a fixed dose of 0.4 mCi/kg 90YIT on day −7. FC chemo was then administered at the same dose and schedule (days −5 to −3) as described above. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days −2, −1 in pts receiving an unrelated or HLA-mismatched donor. Results: A. Transplant with FCR. Median age was 53 years (range, 33–68) years. Median prior treatments was 3 (range, 2–7). At transplant, 96% had chemosensitive disease (38% CR, 62% PR); 15% were PET+; and 53% had IPI = 0. Forty five pts (96%) had a transplant from a matched sibling donor, and 2 from unrelated ones. Since the last update (Blood 2008), one pt had recurrent disease (responded to donor lymphocytes + rituximab); three deaths occurred while pts were in CR: one because of pancreatic cancer (with strong family history), one of infection, and one of unknown causes. With a median follow-up time of 107 months (range, 72–142), the OS and PFS rates at 10-year were 78% (95%CI, 62–87) and 72% (95% CI, 56–83), respectively. Lymphoma-free OS and PFS rates were 82% and 76%, respectively. B. Transplant with 90YIT-FC. Compared to the FCR group, more pts within this group had refractory disease (non-responding or progressing with chemo-immunotherapy) at transplant (38% vs 4%, respectively, p<0.001), were PET+ {44% vs 15%, respectively, p=0.01; (expert review by H.A.M)}, and more had a matched unrelated or mismatched transplant (43% vs 4%, respectively, p <0.001). Other characteristics such as age, number of prior chemotherapy regimens, time from diagnosis to transplant, were not significantly different between the two groups. With a median follow-up of 23 months (range, 7–70), the 2-year OS and PFS rates were 88% and 85%, respectively, not statistically different from the 2-year OS and PFS of the FCR group (83% and 85%, respectively) (p=0.9) (Figure). The 2-year PFS rates for pts with refractory and sensitive disease were 80% and 87%, respectively (p=0.7). Findings after the 111In-ibritumomab scans (40% were positive) did not impact outcomes. The incidence of acute II-IV GVHD was 13% in FCR- and 23% in the 90YIT-FC group (p=0.2); the rates of acute III-IV GVHD were 2% and 8%, respectively; p= 0.3. We noticed an unexpected trend for a lower incidence of chronic extensive GVHD in the 90YIT-FC group (24% vs 40%, respectively, p=0.3), despite the higher proportion of unrelated transplants in that group. Conclusions: Nonmyeloablative allogeneic transplant can induce complete responses lasting over a decade in the majority of patients with relapsed follicular lymphoma. The addition 90YIT to the regimen appears to be particularly effective in relapsed refractory patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hodgkin lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8,500 new patients annually and representing approximately 11% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence are used to optimize therapy for patients with limited or advanced stage disease. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. High-dose chemotherapy (HDCT) followed by an autologous stem-cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered.

Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after

Introduction: The first series of patients with metastatic renal cell carcinoma (RCC) treated by non-myeloablative allogeneic hematopoietic cell transplantation (HCT) was reported in 2000 and demonstrated an allogeneic graft-versus-tumor (GVT) effect that encouraged further investigation of this approach. However, the past 10 years have also witnessed profound changes in the medical management of metastatic RCC with the introduction of targeted therapies directed against VEGF or mammalian target of rapamycin (mTOR) signaling pathways creating uncertainty about a continued role for allogeneic HCT in the treatment of RCC.Areas covered: A total of 21 published reports describing clinical outcomes for 398 patients with metastatic RCC treated by allogeneic HCT compiled herein provide a composite overview of the world wide experience for key efficacy and toxicity outcomes. Review of correlative studies that identify donor-derived T cells as mediators of RCC-specific GVT effects offers insight into both the potential as well as the technical barriers to the delivery of antigen-specific post-transplant cellular therapy or vaccination designed to augment the allogeneic GVT effect.Expert opinion: The future development of non-myeloablative allogeneic HCT for metastatic RCC will require novel treatment protocols designed to augment and sustain post-transplant GVT effects against RCC to generate renewed enthusiasm for this approach.

Cancer Immunotherapy

Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.

Y-90-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for High-Risk B-Cell Lymphoma

AbstractAbstract 33 Purpose:Non-myeloablative allogeneic transplantation (NMAT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. We hypothesized that 90Y-ibritumomab tiuxetan-based NMAT would safely facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft which would also abrogate the hematologic toxicity of the RIT. Patients and Methods:Forty patients with relapsed, high-risk B-NHL and persistent disease who were not deemed appropriate for standard NMAT due to disease factors and not considered appropriate for myeloablative transplant due to age, pretreatment, or co-morbidities were enrolled in this phase II trial. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from matched related (n=15) or unrelated (n=25) donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Baseline features included: median age = 58 years (range 29–69 years), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 (range 5.2–18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40–95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0–10), pretransplant IPI ≥3=21 (53%). Histologies included: DLBCL (14, including 6 that had transformed from indolent disease), CLL/SLL (10), mantle cell lymphoma (8), FL (6), hairy cell leukemia (1), and marginal zone lymphoma (1). Results:Early objective responses attributable to the conditioning regimen at 1 and 3 months were observed in 19 (48%, 3 CR/CRU, 16 PR) and 24 (60%, 13 CR/CRU, 11 PR) patients, respectively, including 17 (59%) objective responses in the 29 patients with known chemoresistant disease and 10 (59%) of 17 with bulk > 5cm. In total, 33 (83%) patients experienced reduction in the measurable disease burden by day 84. The estimated OS and PFS at 30 months were 54.1%, and 31.1%, respectively. The regimen was well tolerated and all patients experienced sustained engraftment with no graft rejection. The neutrophil and platelet nadirs were 50/μ L and 12,000/μ L and occurred a median of 12 and 8 days after transplant, respectively. The median duration of neutropenia <500/μ L was 11 days and thrombocytopenia < 50,000/μ L was 8 days. Grade III acute GVHD occurred in 4 patients (10%) but none had grade IV. Chronic extensive GVHD occurred in 8 patients (20%). Non-relapse mortality at 100 days and 30 months were 2.5% and 15.9%, respectively. Multivariable analysis identified early response (p<0.001), baseline platelet counts >25,000/μ L (p=0.002), indolent histology (p<0.001), and related donors (p=0.04) as associated with improved survival. Conclusions:The addition of 90Y-ibritumomab tiuxetan to NMAT is safe, feasible, and can be readily employed yielding early responses and prolonged disease control in a subset of the highest risk B-NHL patients. Disclosures:Gopal:Biogen-Idec: Research Funding. Off Label Use: Zevalin for transplant conditioning. Maloney:Spectrum: Consultancy, Honoraria; Genetech: Consultancy, Honoraria.

Impacts of Cytogenetic Abnormalities and Prior Alemtuzumab on Outcomes of Patients (pts) with High-Risk Chronic Lymphocytic Leukemia (CLL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT)

AbstractAbstract 2364Allogeneic HCT using nonmyeloablative regimens may provide long-term remission in high-risk relapsed CLL. Here, we investigated the impact of histology, disease status, lymph node (LN) size, genomic aberrations, donor type, and prior alemtuzumab on outcomes. Pts (n=136) were conditioned with 2Gy TBI alone (12%) or 2Gy TBI plus 90 mg/m2 fludarabine (88%). Median age was 56 (range 42–72) years and median number of prior regimens was 4. Ninety percent of pts had fludarabine-refractory CLL. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic extensive GVHD was 51%. Complete (CR) and partial remissions (PR) were seen in 55% and 15% of pts, respectively. Estimated 5-years rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 32%, 36%, 41%, and 32%, respectively. Overall, 58 pts are alive; 45 in CR, 5 in PR, 5 with stable disease, and 3 with progression (PD)/relapse. Univariate outcomes (Table 1) were not statistically significantly different between donor types for NRM (p=0.37), relapse (p=0.17), or PFS (p=0.88). Pts with CLL and SLL had comparable rates of relapse and PFS. Disease status at HCT had no impact on NRM (p=0.75), relapse (p=0.31), or PFS (p=0.27). Relapse (p=0.51) and PFS (p=0.45) were not statistically significantly different among the 6 groups of cytogenetic abnormalities (Table 1). Both alemtuzumab within 12 months before HCT (53% vs. 31%, p=0.007, Figure) and LN size ≥5 cm (59% vs. 28%, p=0.003) were associated with increased rates of relapse. In Cox regression model for outcomes, prior alemtuzumab (HR: 2.20, p=0.02) and LN size ≥5 cm (HR: 2.21, p=0.02) were independently associated with increased relapse; while donor type, cytogenetic abnormalities, and disease status were not. PFS was also worse for pts with prior alemtuzumab (HR: 1.55, p=0.09) and LN size ≥5 cm (HR: 1.64, p=0.06). In multivariate models, pts who had alemtuzumab within 3 months prior to HCT appeared to have the highest relapse risk (Table 2). Prior alemtuzumab had no impact on CD3 donor chimerism following HCT. Further studies are warranted to explore whether the negative impact of alemtuzumab on relapse was due to unrecognized high-risk disease features or hampering the quality of graft-versus-tumor effects such as by deletion of host dendritic cells (Blood. 2002; 99: 2586). Allogeneic nonmyeloablative HCT is associated with graft-versus-leukemia effects even against chemo-refractory and high cytogenetic-risk diseases. We currently are studying novel approaches to better debulk disease before HCT and/or to augment graft-versus-leukemia effects after HCT for CLL pts with large LN size.Table 1:Univariate outcomes in 136 patients with CLL receiving nonmyeloablative HCT5 year outcomes (%)FactorGroupNNRMRelPFSDonorHLA-matched related75264331HLA-matched unrelated53422434HLA-antigen mismatched8155629p-value0.370.170.88Disease status at HCTChemo-responsive55313238Chemo-refractory72324127Untested relapse9362242p-value0.750.310.27Cytogenetic abnormalitiesNormal39422534Del17p24493218Del11q19314029Tri1210204040Del13q18174340Other26214733p-value0.250.510.45Alemtuzumab within 12 months before HCTNo103343135Yes33225325p-value0.800.010.07LN size<5 cm36302839≥5 cm100335911p-value0.950.0030.01Note: p-values reflect underlying hazard ratios over all follow-up period. [Display omitted] Disclosures:Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.

Human-Leukocyte-Histocompatibility Antigens Predict Response to Rituximab and Donor Lymphocyte Infusion (DLI) After Non-Myeloablative Allogeneic Stem Transplantation (NST) for Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 2548 Background:The effectiveness of allogeneic NST in CLL has been attributed to a graft-versus-leukemia effect due to elimination of tumor cells by alloimmune effector lymphocytes. In a previous study (Khouri et al, Exp Hematol 2004), we found that when patients with CLL develop relapse after NST, immunomanipulation (IMM) via withdrawal of immunosuppression and DLI with rituximab can induce sustained remissions in some patients. The underlying mechanism of this GVL effect is unknown. The simultaneous presence of the killer-immunoglobulin-like receptor (KIR) 3DL1 and its corresponding human leucocyte antigen (HLA) class I ligands bearing the Bw4 epitope has been described in CLL (Verheyden S, Leukemia 2006). Purpose:Considering that the HLA class I molecules may act as restriction elements for GVL targets after NST in CLL, we investigated the potential association of certain common class I HLA alleles and response to IMM. Methods:We studied all 43 CLL pts who required IMM after NST in sequential phase II protocols at the U.T. MD Anderson Cancer Center from February 1996 to August 2007 because of persistent disease or because of progression. In our analysis, we examined the most common alleles and serotypes expressed in the patients studied. This included HLA-A1, A2, A3, A24, B7, B8, B35, B44, B60, B62, BW4, BW6, CW7. These allele groups are known to be common in most world populations. Rituximab was given at a dose of 375 mg/m2 intravenously followed by 3 weekly doses of 1000 mg/m2. A DLI of 1 × 107 CD3-positive T cells/kg was given after the first two doses of rituximab if no GVHD occurred. An escalated DLI dose was given at 6-week intervals if there was persistent active disease and no GVHD. Results:Median age (range) was 55 years (39-73) and the median Hematopoietic Stem Cell Comorbidity Index was 3 (range, 0–8). The median number of prior chemotherapies was 3. At their transplant, 48% of pts had refractory disease, 90% had Binet stage B/C, and 60% had a beta-2 microglobulin of =/> 3. P53 deletion was detected in 11 of 35 pts (31%) tested. Mixed T-cell chimerism was observed in 60 % of pts at day 90. The median number of DLI infused was 2 (range, 1–6); their median maximal dose was 43.6 (range, 1–200) × 106 CD3+/Kg. In these 43 pts, 20 (47%) experienced complete remission (CR), by CT scans, marrow and flow analysis. Pts characteristics at time of study entry (described above) for NST, and at the time of initiation of IMM (this included white blood cell counts, LDH, % lymphocyte in marrow, % CD5-CD19, lymph node size by computed tomography, maximum dose DLI, number of DLIs, GVHD prior IMM and grade, T-cell chimerism), as well as HLA subtypes were assessed. The major determinants to achieve CR following IMM included receipt of a PBSC graft and achievement of a good (> 90%) donor T-cell chimerism at day 90 (p = 0.035), and having a combination of HLA-A1-positive, HLA-A2-negative, and HLA-B44-negative (p= 0.0009). The rate of CR to IMM was 9%, 36%, 50%, 91% respectively in patients who had none of the HLA factors described, I, 2, and all 3 respectively. There was no statistically significant difference in pts and disease characteristics between HLA-A1-positive or negative, HLA-A2 positive or negative nor between HLA-B44-positive or negative pts. In addition the risks of acute II-IV [Cumulative incidence (CI)=23%) and chronic GVHD (CI=69%) were not different between the respective subtypes. With a median follow-up in surviving pts of 37.2 months (range, 11.4–131.1), the progression-free survival rates at 5-year for patients with HLA-A1+/A2-/B44- vs those who had none of those HLA types were 68% vs 15%, respectively, (p<0.0001). Conclusions:Our results represent the first report showing certain HLA alleles might be predictive for response to GVL and achieving long-term remission in CLL. Verification of our findings in a larger cohort of pts is highly warranted for better selecting pts for IMM for the treatment of recurrent malignancy in CLL. Disclosures:No relevant conflicts of interest to declare.

Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies

AbstractAbstract 3541We have previously shown that SCT from HLA-haploidentical related donors (HAPLO) after nonmyeloablative conditioning is feasible with a low incidence of grade III-IV acute GVHD or treatment-related mortality (TRM) (Rizzieri et al. JCO 2007). We now report our comparative study in patients who received SCT from a 6/6 HLA-matched related (MRD), 8–10/8 HLA-matched unrelated (MUD), or HAPLO donor, after nonmyeloablative conditioning. Methods:Patients with chemosensitive relapse or high risk disease with minimal residual disease at study entry were eligible. The conditioning regimen consisted of fludarabine, 40 mg/m2 for 4 days; melphalan, 140 mg/m2 for 1 day; and alemtuzumab, 20 mg for 4 days for patients with lymphoid or myelomatous diseases. Fludarabine and alemtuzumab at the same doses with busulfan, 130 mg/m2 for 2 days was used for patients with myeloid diseases. Mycophenolate mofetil was used for GVHD prophylaxis. Donor lymphocyte infusions were performed in 15 MRD patients and 4 HAPLO patients. Disease-free survival (DFS) and overall survival (OS) rates after SCT were estimated using the Kaplan–Meier method, and univariate comparisons were performed using the log-rank test. Cox proportional-hazards regression was used to evaluate variables that potentially affected the survival rates. Results:The lymphoid cohort included 52 patients with ALL (n = 6), lymphoma (n = 42), or myeloma (n = 4), whereas the myeloid cohort included 46 patients with AML/MDS (n = 40), and myeloproliferative disorder (MPD) (n = 6). The median subject age was 56.5 (range, 20–73) years with a median follow-up of 15 months among survivors. A total of 29, 40, and 29 patients received transplants from MRD, MUD, and HAPLO, respectively. All 29 patients engrafted after HCT from MRD. One of 40 patients who received SCT from MUD had a primary graft failure (GF), with 2 secondary GF and 1 early relapse. Two of them were rescued by subsequent nonmyeloablative SCT from the same MUD or new HAPLO donor. Among 28 HAPLO patients evaluable for engraftment, 8 had a primary GF, 6 of these had myeloid disease; 2 additional patients had donor cell recovery but without full recovery of normal blood counts. Three of the 8 were rescued with subsequent nonmyeloablative SCT from the same donor. The transplant regimen resulted in 11% TRM at day 100. Grade III-IV acute GVHD rates were 0/29 (0%), 4/40 (10%), and 5/29 (17%) in patients who received a transplant from a MRD, MUD, or HAPLO, respectively. CMV reactivation occurred in 57% of patients and 6% developed CMV disease. Other infectious complications included polyomavirus in 24% of patients, bacteria in 23%, respiratory viruses in 13%, and fungal infections in 7%. The common causes of death were progressive disease (30% for all cause of death) and infections (32%). The 1-year DFS rate after SCT from MRD, MUD, and HAPLO was 55% (95% CI, 33–73%), 39% (22–56%), and 34% (16–53%), respectively (Log-rank test, P = 0.094) (Figure 1); the corresponding 1-year OS rate was 66% (43–82%), 39% (21–55%), and 34% (16–53%), respectively (Log-rank test, P = 0.012) (Figure 2). Multivariate analysis revealed that SCT from MUD/HAPLO, compared with that from MRD, was the only adverse factor that affected the OS rate (HR for MUD, 2.62 (95% CI, 1.15–5.96), P = 0.022; HR for HAPLO, 3.17 (1.36–7.37), P = 0.007), but the OS rate after SCT from HAPLO did not significantly differ from that after SCT from MUD (P = 0.560). Other variables (recipient age, conditioning regimen, and disease status at transplant) were not significantly associated with the outcome. [Display omitted] Conclusions:The results show the feasibility of this approach with this regimen and the clinical outcomes in patients who received transplants from HAPLO are comparable to patients who received transplants from MUD. Development of strategies to improve immune recovery remains a current challenge. Disclosures:Off Label Use: Alemtuzumab for conditioning in allogeneic stem cell transplantation. Horwitz:Genzyme: Honoraria, Research Funding. Chao:Genzyme: Research Funding. Rizzieri:Genzyme: Speakers Bureau.

Therapeutic concepts in mantle cell lymphoma

Mantle cell lymphoma has been considered an incurable disease with current chemotherapy regimens. Recent intense chemoimmunotherapy induction regimens with or without consolidation with autologous stem cell transplantation procedures are showing a potential for cure in a sizable fraction of patients. Similarly, in the salvage setting, preliminary experience with non-myeloablative allogeneic transplant may cure some patients even after multiple therapeutic failures. However, the recent knowledge of the three basic biologic derangements that are integrated in the disease may change the therapeutic approach of the disease in the near future. In fact, new drugs that target more specifically the major molecular alterations of the disease are being progressively incorporated into the therapeutic armamentarium of the disease. In the near future, more individualized approaches that will take into account not only risk factors present at diagnosis but also biomarkers representative of the molecular alterations present in the disease are foreseen. In this review, we are going to discuss the current therapeutic approaches and the main new drugs that target more specifically the major molecular pathways alterations of the disease.

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4–1147) days, the median PFS was 100 days (95% confidence interval (CI), 66–128 days), and median OS was 209 days (95% CI, 128–236 days). Patients with chronic GVHD had better survival—median OS 426 days (95% CI, 194–NE days) vs 143 days (95% CI, 114–226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

Relapsing acute myeloid leukemia beginning with a penile localization

We report the case of a 52-year-old man who was diagnosed for an acute myeloid leukemia (FAB classification: M1) with abnormalities in conventional caryotype showing trisomy 7 and recombination of MLL-AML1. His leukemia was discovered in front of neutropenic fever and circulating blastic cells. He was first treated with three cycles of intensive chemotherapies using high doses of cytarabine and idarubicine in association, followed by a nonmyeloablative allogeneic bone marrow-related transplantation based on busulfan and fludarabine conditioning. He relapsed 2 months later with pancytopenia and was, therefore, treated with a myeloablative bone marrow-related transplantation using melphalan 200 mg/m conditioning. He stayed in complete clinical and cytological remission for 16 months, without any signs of GVHD. He then started to complain of a painfull spot on his penis. On examination, he had first a nodular painful lesion of the dorsal side of the penis, with no contiguous lymph nodes. No peripherical or medullar blastic infiltration was seen. Axial and sagittal fused FDG PET-CT images showed an intense and isolated FDG uptake of the distal corpus cavernosa (Image 1A). A surgical excision with anatomopathological analysis confirmed the leukemic origin of the lesion showing myeloblastic cells CD34 1 (Image 1B). The margins were safe from leukemia cells. However, even before beginning a treatment, he relapsed with a bilateral infiltration of corpus cavernosa, the penile skin, and an inguinal adenopathy. Because surgery did not limit the extension of leukemia as already report, treatment consisted in an association of a systemic donor lymphocytes injection with gemtuzumab ozogamicin (at 3 mg/ṁ) and a local radiotherapy at 40 Gy on penis and 30 Gy onto the inguinal lymph node areas, seen on sagittal CT-scan (Image 1C). A complete local remission was observed, but 3 months later, a new relapse in the gums was observed. A palliative therapy was begun, but he died 2 months later from a severe dyspnoea, due to a blastic localization in oropharynx and blastic hyperleucocytosis at 50G/L. To date, only five cases of penile localization of acute leukemia have been listed: two of them were AML [1,2]. There were all FAB M4 subtype, and the penile metastasis was seen at relapse. The first patient was treated with radiotherapy exclusively and the second by surgery, but the two patients died for disseminated disease. Three others Image 1. A: Sagittal and axial FDG PET-CT, with fused images, showing intense nodular FDG uptake of the distal corpus cavernosa. B: Massive tissue infiltration by myeloblastic cells, confirmed by positive CD34 staining. C: First dosimetry planning for radiotherapy treatment. Sagittal CT-scan showing important oedema of all the penis. Radiotherapy treatment neaded two other dosimetry planning due to the good results it gave.

Progress in allogeneic transplantation for multiple myeloma

Allogeneic hematopoietic stem cell transplantation to treat multiple myeloma has been attempted since the early 1980s. The original conditioning regimen including high-dose total body irradiation (TBI) plus cyclophosphamide was myeloablative and associated with a relatively low relapse/progression rate, but high transplant-related mortality and no obvious improvement in progression-free survival or overall survival. Some risk groups may benefit from this transplant modality and occasional patients may be cured, but due to the high-transplant-related mortality it is mainly abandoned. Reduced intensity conditioning (RIC), non-myeloablative allogeneic transplantation reduces transplant-related mortality significantly when compared with myeloablative conditioning, but the relapse/progression rate is somewhat higher. However although the treatment-related mortality is higher than after autologous transplantation, the progression-free and overall survival was better or tended to be better in three of five prospective trials comparing tandem autologous/RIC allogeneic transplantation to single or tandem autotransplantation due to lower relapse/progression rate. Adding donor lymphocyte infusions post-transplant, new drugs like bortezomib, thalidomide, lenalidomide or pomalidomide pre- and/or post-transplant, and more specific antimyeloma cell therapy like NK cells post-transplant, may in future studies prove to improve results.

Treatment of older patients with de novo acute myeloid leukemia (AML) with one or more postremission chemotherapy courses: Analysis of four CALGB studies.

6531 Background: AML in older patients is rarely cured by chemotherapy, but treatment is given to induce complete remission (CR) and prolong disease-free and overall survival (DFS, OS). Optimal post-CR chemotherapy has not been defined. We analyzed outcomes in previously untreated de novo AML patients ≥ 60 years (n = 1,525) among 4 consecutive CALGB trials using different consolidation regimens. A randomized trial (8923) produced similar results using 2 courses of cytarabine (AraC) 1 g/m2 x 5 days plus mitoxantrone 10 mg/m2 x 3 days compared to 4 courses of AraC at 100 mg/m2 x 5 days (Blood 2001;98:548). CALGB 9720 used ADE induction (AraC 100 mg/m2, daunorubicin 60 mg/m2 and etoposide 100 mg/m2 for 7, 3 and 3 days) with only a single post-remission course of the same drugs and doses for 5, 2 and 2 days. Methods: Results of 9720 were compared with results from similar patient populations treated on 3 other CALGB trials that used more than one post-CR course – either 4 courses (8525, 8923) or 2 intensified courses (8923, 10201). Results: The CR rate on 9720 did not differ compared to the other trials (52 vs. 53%), but DFS was significantly shorter (medians, 7.0 vs. 9.3 mos; p = 0.002), while OS did not differ (median, 8.4 mos), nor did survival following attainment of CR (13.9 vs. 14.5 mos; p = 0.13). DFS was shorter on 9720 for patients both 60-69 (n = 480; 6.9 vs. 9.3 mos; p = 0.02) and 70-79 (n = 294; 7.4 vs. 10.3 mos; p = 0.04) years; there were too few CR patients ≥ 80 years (n = 20) to allow a reliable conclusion. Conclusions: This historical comparison suggests that a single consolidation course results in significantly shorter DFS for de novo AML patients ≥ 60 years, but has no effect on OS nor survival following attainment of CR. The value of administering additional consolidation courses to prolong DFS without an effect on OS is debatable. Outcomes within cytogenetic and molecular subsets as well as quality of life measurements would be of interest. DFS and OS have remained short among older AML patients over the 25-year period covered by these studies; experimental approaches, including nonmyeloablative allogeneic hematopoietic cell transplantation in appropriate patients, are thus warranted. No significant financial relationships to disclose.

Tandem autologous non-myeloablative allogeneic transplantation in patients with multiple myeloma relapsing after a first high dose therapy

We retrospectively studied a series of 23 patients (median age 50 years, range 29-59 years) with multiple myeloma (MM), treated in first relapse by a sequential autologous-allogeneic tandem approach. Tandem transplantation (TT) consisted in high dose melphalan (HDT) and auto-SCT followed by an (allo-SCT) preceded by two gray TBI non-myeloablative conditioning. All patients received a first HDT as frontline treatment. At day 100 post allo-SCT, complete donor chimerism was detected in 22 patients (95%). Acute GVHD was observed in 19 patients (15 grade I-II (65%) and 4 grade III-IV (17%)). Ten patients (43%) developed an extensive chronic GVHD. The non-relapse mortality at 1 year was 17%. After TT, the overall response rate was 91% (17% partial response, 35% very good partial remission and 39% complete remission). At 2 years, OS was 61%. Median event-free survival and OS were 36.8 and 60 months, respectively. Based on the propensity score matching method, a significant survival advantage could be seen in patients treated with TT as compared with non-allografted patients. Thus, allo-SCT, in TT approach, provides a high response rate with low toxicity and may improve survival of patients with relapsing MM.