Hodgkin lymphoma (HL) represents one of the great success stories in hematology going from a uniformly fatal disease, to one that is curable in the vast majority of cases. Despite this success, some patients experience relapse. To address this unmet need a variety of agents, classes of drugs, and strategies have demonstrated activity in HL recurring after autologous hematopoietic stem cell transplantation. These include chemotherapeutics (gemcitabine-based combinations, bendamustine), histone deacetylase (HDAC) inhibitors (panobinostat), immunomodulatory agents (lenalidomide), mTOR inhiobitors (everolimus), monoclonal antibodies (rituximab), and antibody-drug conjugates (brentuximab vedotin) as well the potential of long-term disease control via allogeneic transplantation. Such advances reflect our increased understanding of the biology of HL and hold promise for continued improved outcomes for those suffering with this condition.

Purpose

Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that down-modulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.

Experimental Design

The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified and compared in studies using athymic mice bearing Ramos lymphoma xenografts.

Results

Biodistribution studies demonstrated delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by 111In-DOTA-bis-biotin (6.2 ± 1.7 % of the injected dose per gram [%ID/gm] of tumor 24 hours after Y43A-SAv FP and 5.6 ± 2.2 %ID/g with S45A-SAv FP) than in mice on normal diets pretargeted with WT-SAv FP (2.5 ± 1.6 %ID/g; p = 0.01). These superior biodistributions translated into superior anti-tumor efficacy in mice treated with mutant FPs and 90Y-DOTA-bis-biotin (tumor volumes after 11 days: 237 ± 66 mm3 with Y43A-SAv, 543 ± 320 mm3 with S45A-SAv, 1129 ± 322 mm3 with WT-SAv and 1435 ± 212 mm3 with control FP [p < 0.0001]).

Conclusions

Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for both myelodysplastic syndromes (MDS) and lymphoid malignancies. Little is known about the efficacy of allogeneic HCT in patients in whom both myeloid and lymphoid disorders are present at the time of HCT. We analyzed outcomes in 21 patients with MDS and concurrent lymphoid malignancy when undergoing allogeneic HCT. Seventeen patients had received extensive prior cytotoxic chemotherapy, including autologous HCT in seven, for non-Hodgkin lymphoma (NHL, n=7), Hodgkin lymphoma (HL, n=2), chronic lymphocytic leukemia (CLL, n=5), NHL plus HL (n=1), multiple myeloma (n=1), or T-cell acute lymphocytic leukemia (ALL) (n=1), and had, presumably, developed MDS as a consequence of therapy. Four previously untreated patients had CLL. Nineteen patients were conditioned with high-dose (n=14) or reduced-intensity regimens (n=5), and transplanted from HLA-matched or one antigen/allele mismatched related (n=10) or unrelated (n=9) donors; two patients received HLA-haploidentical related transplants following conditioning with a modified conditioning regimen. Currently, 2 of 4 previously untreated, and 2 of 17 previously treated patients are surviving in remission of both MDS and lymphoid malignancies. However, the high non-relapse mortality among previously treated patients, even with reduced-intensity conditioning regimens, indicates that new transplant strategies need to be developed.

Purpose

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown.

Patients and Methods

To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.

Results

The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.

Conclusion

An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.

The structural maintenance of chromosome 1 (Smc1) protein is a member of the highly conserved cohesin complex and is involved in sister chromatid cohesion. In response to ionizing radiation, Smc1 is phosphorylated at two sites, Ser-957 and Ser-966, and these phosphorylation events are dependent on the ATM protein kinase. In this study, we describe the generation of two novel ELISAs for quantifying phospho-Smc1Ser-957 and phospho-Smc1Ser-966. Using these novel assays, we quantify the kinetic and biodosimetric responses of human cells of hematological origin, including immortalized cells, as well as both quiescent and cycling primary human PBMC. Additionally, we demonstrate a robust in vivo response for phospho-Smc1Ser-957 and phospho-Smc1Ser-966 in lymphocytes of human patients after therapeutic exposure to ionizing radiation, including total-body irradiation, partial-body irradiation, and internal exposure to 131I. These assays are useful for quantifying the DNA damage response in experimental systems and potentially for the identification of individuals exposed to radiation after a radiological incident.

Purpose

Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD).

Patients and Methods

We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive.

Results

Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT.

Conclusion

These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.

We conducted a multi-center phase II trial of gemcitabine (G), carboplatin (C), dexamethasone (D), and rituximab (R) in order to examine its safety and efficacy as an outpatient salvage regimen for lymphoma. Fifty-one patients received 2–4 21-day cycles of G (1000mg/m2, days 1 and 8), C (AUC=5, day 1), D (40mg daily days 1–4), and R (375mg/m2, day 8 for CD20 positive disease) and were evaluable for response. Characteristics included: median age 58y (19–79y), stage III/IV 88%, elevated LDH 33%, median prior therapies 2, prior stem cell transplant 12%, chemoresistant 62%, median prior remission duration 2.5 months. The overall and complete response rates were 67% (95% confidence interval [CI], 54–80%) and 31% (95% CI 19–44%), respectively, with activity seen in a broad variety of histologies. Responses occurred in 16 of 17 (94%, 95% CI 83–100%) transplant eligible patients and 15 of 28 (54%, 95% CI 34–71%) with chemoresistant disease. The median CD34 yield in patients attempting peripheral blood stem cell (PBSC) collection following this regimen was 10.9 × 106 CD34+ cells/kg (range, 5.0 – 24.1 × 106). Hematologic toxicity was common but febrile neutropenia (2.5%) and grade 4 non-hematologic adverse events (n=2) were rare with no treatment-related deaths. GCD(R) is a safe and effective outpatient regimen for relapsed lymphoma and successfully mobilizes PBSC.

The finding of umbilical metastasis has historically been called a “Sister Mary Joseph Nodule”. A few case reports of lymphoma presenting in this manner have been documented. We report a case of relapsed mantle cell lymphoma (MCL) presenting as a Sister Mary Joseph's nodule. Although the few reports of lymphoma exhibiting umbilical metastasis suggest that patients may still expect a reasonable response to chemotherapy, this patient experienced multiple relapses, despite aggressive chemotherapy regimens. This clinical course is characteristic of the mantle cell form of non-hodgkin's lymphoma and illustrates a need to seek out more effective therapies.

Radioimmunotherapy (RIT) for treatment of hematological malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled-DOTA-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal blood-pool activity, whereas directly-labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments demonstrated that 90Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared to mice treated with conventional RIT using 90Y-labeled anti-hCD45 Ab at 200 μCi. Since human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 hours, 27.3 ± 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using 131I-A20-Ab compared with 40.0 ± 5.4% ID/g for pretargeted 111In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.

We analyzed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at three years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group had a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P=.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.

Background

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL since there are few established therapies for these patients.

Patients and Methods

Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included: median age = 35 years (range, 14–59 yrs), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens and 38 (59%) underwent non-TBI conditioning.

Results

The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively, (median follow-up = 4.2 years). Multivariable analysis only identified year of transplant as independently associated with improved OS (p=.008) and PFS (p=.04), with patients transplanted in later years having better outcome. The probabilities of 3-year PFS for patients transplanted between 1986–1989, 1990–July 1993, August 1993–1999, and 2000–2005 were 9%, 21%, 33%, and 31%, respectively.

Conclusions

These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL pts, with improved outcomes in patients transplanted more recently.

Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT’s efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: 1. Myeloablative doses of RIT with or without chemotherapy, and 2. Standard non-myeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of I-131-Tositumomab (Bexxar), Y-90-ibritumomab tiuxetan (Zevalin), and I-131-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of Y-90-ibritumomab tiuxetan or I-131 Tositumomab plus BEAM chemotherapy followed ASCT. RIT targeting CD-45, CD-33 and CD-66 prior to allogeneic transplantation has also been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.

Reduced-intensity-conditioning (RIC) prior to allogeneic hematopoietic cell transplantation (HCT) is increasingly employed as a potentially curative option for patients with advanced lymphoma; however relapse remains a major challenge. Unfortunately, little data exist on the outcomes, predictors of survival, and results of specific management strategies of such individuals. One-hundred-one consecutive relapses occurred and were evaluated in 280 lymphoma patients following RIC-HCT. Characteristics included: aggressive non-Hodgkin lymphoma (NHL) (n=42), indolent NHL (n=33) and Hodgkin’s Lymphoma (HL) (n=26). Median time to relapse was 90 (range 3 - 1275) days and graft-versus-host-disease at relapse was present in 56 (55%) patients. Interventions following relapse included no therapy (n=14), withdrawal of immunosuppression alone (n=11), chemoradiotherapy (n=60), and donor lymphocyte infusion/second HCT (n=16). Overall survival (OS) at 3 and 5 years following relapse was 33% (95%CI 23-44%) and 23% (95%CI 13-34%), respectively. Aggressive NHL (vs indolent disease, HR=2.29, p=.008) and relapse <1 month after HCT (vs >6 months HR=3.17 p=.004) were each associated with increased mortality. Estimated 3-year OS after relapse for aggressive, indolent and HL was 16% (95%CI 5-32%), 40% (95%CI 19-61%) and 47% (95%CI 29-64%), respectively. The 1-year survival for patients relapsing within 1 month of HCT was 24% as compared to 52%, 74%, and 77%, for those relapsing at 1-3 months, 3-6 months, and >6 months after HCT. We conclude that despite relapse of lymphoma after RIC-HCT, some patients can experience prolonged survival with better post-relapse outcomes occurring in patients with indolent NHL, HL or late relapse.