Bortezomib and Vorinostat Therapy as Maintenance Therapy Post Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen.

INTRODUCTION: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin's lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for Multiple Myeloma (MM) showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. METHODS: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan (R-BEAM)/carmustine, etoposide, cytarabine, melphalan (BEAM). After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. RESULTS: Nineteen patients received BV post ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. CONCLUSIONS: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.

Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis.

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.

TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice.

Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.

Radiographic Response of Solitary Plasmacytomas After Conformal Radiotherapy May Be Delayed: Outcomes in the 3D Era.

OBJECTIVE: Although recurrence rates after radiotherapy for solitary plasmacytoma (SP) are well established, little is known about how SP responds radiographically, as most historical patients were treated in the 2D era. We evaluated the response to radiotherapy among SP patients staged and treated with 3D techniques, including proton therapy, which has not yet been previously reported. METHODS AND MATERIALS: Between 2007 and 2021, 15 SP patients (4 extramedullary, 11 bone) staged with 3D imaging and bone marrow evaluation were consecutively treated with definitive radiotherapy. The best response was categorized in 9 evaluable patients according to response evaluation criteria in solid tumors (RECIST) and positron emission tomography response criteria in solid tumors (PERCIST). RESULTS: With a median follow-up of 34 months, 4 patients relapsed. The median time to the best response was ~2 years (26.6 mo RECIST, 25.4 mo PERCIST). Response rates differed based on response assessment criteria. PERCIST was associated with higher rates of complete (85.7%) or partial response (14.3%) compared with RECIST (16.7% complete, 33.3% partial). Two-year and 4-year PFS for extramedullary SP were 100% and 75%, compared with 91% and 55% for bone ( P =0.75). Patients treated with proton therapy (n=5) did not appear to have different patterns of relapse (1 marginal, 1 distant) compared with those treated with photons or electrons (n=10; 2 distant). CONCLUSIONS: More conformal dose distribution with proton therapy does not appear to alter patterns of recurrence. Although response rates differ based on criteria by both RECIST and PERCIST assessments, the radiographic response may be slow and requires validation in other cohorts.

Successful Mobilization of Autologous Hematopoietic Peripheral Blood Stem Cells after Salvage Chemotherapy in Patients with Low CD34 Blood Cell Counts.

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Diagnosis and Management of Multiple Myeloma: A Review.

IMPORTANCE: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. OBSERVATIONS: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers ß2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients. CONCLUSIONS AND RELEVANCE: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.

Prolonged Lenalidomide Therapy Does Not Impact Autologous Peripheral Blood Stem Cell Mobilization and Collection in Multiple Myeloma Patients: A Single-Center Retrospective Analysis.

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.

A clinical perspective on plasma cell leukemia; current status and future directions.

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/µL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.

A single-center retrospective analysis of outcome measures and consolidation strategies for relapsed and refractory primary CNS lymphoma.

BACKGROUND: Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. METHODS: We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded. RESULTS: During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS. CONCLUSIONS: PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

90Y-labeled anti-CD45 antibody allogeneic hematopoietic cell transplantation for high-risk multiple myeloma.

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 (90Y-DOTA-BC8) as conditioning. 90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation.

BACKGROUND: Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE). PATIENTS AND METHODS: This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL. RESULTS: The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 106 CD34+ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever. CONCLUSION: KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.

A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody, etoposide and cyclophosphamide followed by autologous transplantation, for high-risk relapsed or refractory non-hodgkin lymphoma.

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.

Survivorship after Autologous Hematopoietic Cell Transplantation for Lymphoma and Multiple Myeloma: Late Effects and Quality of Life.

Although autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with lymphoma and multiple myeloma (MM), few studies have addressed late effects and quality of life (QoL) in long-term survivors after AHCT. Using long-term follow-up (LTFU) annual questionnaires with self-reported outcomes, we surveyed 665 patients who were at ≥5 years after AHCT for the diagnosis of lymphoma or MM. Three-hundred and eighty-nine patients completed the questionnaire (58% response rate) at a median of 11 years (range, 5-30 years) after AHCT. The median patient age was 63 years (range, 22-88 years) in the 268 patients with lymphoma and 69 years (range, 34-84 years) in the 121 patients with multiple myeloma. The most commonly reported medical conditions (>10% incidence) were sexual dysfunction, history of shingles, cataracts, osteoporosis or osteopenia, joint replacement, and skin cancer. Current medication use was more frequent in the patients with MM for infection prevention/treatment (19% for MM versus 5% lymphoma; P < .001), hypertension (41% versus 26%; P = .004), osteoporosis (23% versus 10%; P < .001), and pain (32% versus 11%, P < .001). Treated hypothyroidism was more common in lymphoma patients. In multivariate analysis combining lymphoma and MM, worse physical functioning was associated with older age, shorter interval since AHCT, comorbidities, relapse, and treatment for depression and/or pain. Worse mental functioning was associated with younger age and treatment for anxiety, depression, or pain. In conclusion, AHCT survivors report generally good QoL but many late effects and symptoms that are potentially amenable to intervention.

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma.

BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

Phase I Study of a CD45-Targeted Antibody-Radionuclide Conjugate for High-Risk Lymphoma.

PURPOSE: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression. PATIENTS AND METHODS: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose. RESULTS: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later. CONCLUSIONS: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.

Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation.

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.

Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma.

BACKGROUND: Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies. METHODS: This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1-3), and dexamethasone (40 mg PO d 1-4) followed by filgrastim (10 mcg/kg/d sc. through collection). RESULTS: We successfully collected stem cells from all patients, with a median of 7.9×106/kg of body weight (range, 4.4 to 17.3×106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5). CONCLUSION: For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.

Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied. METHODS: We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS). RESULTS: With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease. CONCLUSION: Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen. TRIAL REGISTRATION: ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

Circulating Plasma Cells at the Time of Collection of Autologous PBSC for Transplant in Multiple Myeloma Patients is a Negative Prognostic Factor Even in the Age of Post-Transplant Maintenance Therapy.

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies.