Infusion of autograft natural killer cell/CD14+HLA-DRDIM cell ratio predicts survival in lymphoma post autologous stem cell transplantation.

The infusion of autograft absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are prognostic factors for overall survival (OS) and PFS in non-Hodgkin's lymphoma (NHL) patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). The human monocytic CD14+HLA-DRDIM cells are associated with worse prognosis in NHL. Thus, we investigated whether the autograft A-NKC/A-CD14+HLA-DRDIM ratio predicts survival in NHL. In a total of 111 NHL patients, we analyzed apheresis collection samples for the content of A-NKC and A-CD14+HLA-DRDIM. With a median follow-up of 57.2 months (range: 2.1-84.6 months), patients with an A-NKC/A-CD14+HLA-DRDIM ratio of ⩾0.29 experienced superior OS (5-year OS rates of 84% (95% confidence interval (CI), 72-91%) vs 48% (95% CI, 34-62%), P<0.0002, respectively) and PFS (5-year PFS rates of 59% (95% CI, 47-71%) vs 32% (95% CI, 20-48%), P<0.002, respectively). Multivariate analysis revealed that A-NKC/A-CD14+HLA-DRDIM ratio was an independent predictor for PFS (hazard ratio (HR)=0.56, 95% CI, 0.32-0.96, P<0.03) and OS (HR=0.34, 95% CI, 0.16-0.68, P<0.002). The A-NKC/A-CD14+HLA-DRDIM ratio provides a platform to target specific autograft immune effector cells to improve clinical outcomes in NHL patients undergoing APBHSCT.

A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma.

This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.

Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients.

Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.

IL-10 induces the development of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell non-Hodgkin lymphoma.

The biological role of monocytes and macrophages in B-cell non-Hodgkin lymphoma (NHL) is not fully understood. We have previously reported that monocytes from patients with B-cell NHL have an immunosuppressive CD14(+)HLA-DR(low/-) phenotype that correlates with a poor prognosis. However, the underlying mechanism by which CD14(+)HLA-DR(low/-) monocytes develop in lymphoma is unknown. In the present study, we found that interleukin (IL)-10, which is increased in the serum of patients with B-cell NHL, induced the development of the CD4(+)HLA-DR(low/-) population. Using peripheral blood samples from patients with B-cell NHL, we found that absolute numbers of CD14(+) monocytic cells with an HLA-DR(low/-) phenotype were higher than healthy controls and correlated with a higher International Prognostic Index score. IL-10 serum levels were elevated in lymphoma patients compared with controls and were associated with increased peripheral monocyte counts. Treatment of monocytes with IL-10 in vitro significantly decreased HLA-DR expression and resulted in the expansion of CD14(+)HLA-DR(low/-) population. We found that lymphoma B cells produce IL-10 and supernatants from cultured lymphoma cells increased the CD14(+)HLA-DR(low/-) population. Furthermore, we found that IL-10-induced CD14(+)HLA-DR(low/-) monocytes inhibited the activation and proliferation of T cells. Taken together, these results suggest that elevated IL-10 serum levels contribute to increased numbers of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell NHL.

Bowel perforation in intestinal lymphoma: incidence and clinical features.

BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma. PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features. RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%). CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center.

The underlying plasma cell clones in multiple myeloma (MM) and Ig light-chain amyloidosis (AL) appear to be different not only in terms of 'tumor burden' but also in terms of their underlying biology. High-dose chemotherapy with auto-SCT is one method of reducing the clone size and thereby improving OS. Post-auto-SCT outcomes between the two diseases have never been formally compared. Among all patients with a diagnosis of AL or MM who received auto-SCT as primary therapy at the Mayo Clinic, Rochester, there were higher CR rates (40% versus 29%, P<0.0001) in the AL group. The respective median OS for the AL and MM patients was 113 and 59.5 months, respectively, P<0.0001. Among patients achieving CR, MM patients had a fivefold risk of death as compared with AL patients. Although auto-SCT cannot be offered to all patients with either AL or MM, it appears that for those well enough to be chosen for the procedure, greater benefit is derived among the AL patients. This difference in survival is most notable among those patients who achieve CR, suggesting very different plasma cell biology between the two diseases.

Peripheral blood absolute lymphocyte/monocyte ratio recovery during ABVD treatment cycles predicts clinical outcomes in classical Hodgkin lymphoma.

The peripheral blood absolute lymphocyte/monocyte count ratio at diagnosis (ALC/AMC-DX) predicts survival in classical Hodgkin lymphoma (cHL). However, a limitation of the ALC/AMC-DX is the inability to assess sequentially the host/tumor interaction during treatment. Therefore, we retrospectively examined the ALC/AMC ratio, as a surrogate marker of host immunity (ALC) and tumor microenvironment (AMC), at each adriamycin, bleomycin, vinblastine and dacarbazine treatment cycle as a predictor for clinical outcomes. From 1990 until 2008, 190 cHL patients were diagnosed, treated and followed at Mayo Clinic Rochester and qualified for the study. The ALC/AMC ratio at each treatment cycle was a predictor for overall survival (OS) and progression-free survival (PFS). An ALC/AMC ratio 1.1 versus ALC/AMC <1.1 during treatment cycles was an independent predictor for OS (hazard ratio (HR)=0.14; 95% confidence interval (CI): 0.04-0.40; P<0.0002) and for PFS (HR=0.19; 95% CI: 0.05-0.82; P<0.03). The ALC/AMC ratio during treatment cycles is a predictor for survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during chemotherapy to improve clinical outcomes in cHL.

Impact of lymphocyte and monocyte recovery on the outcomes of allogeneic hematopoietic SCT with fludarabine and melphalan conditioning.

We have recently shown that lymphocyte and monocyte recovery by day +100 are associated with survival post myeloablative allogeneic hematopoietic transplant for acute leukemia. We hypothesized that lymphocyte and monocyte recovery would have a similar impact on survival in the reduced intensity setting. To test this hypothesis, we analyzed clinical data from 118 consecutive fludarabine/melphalan-conditioned patients by correlating peripheral blood absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) at days +15, +30, +60 and +100 with the outcomes. Multivariate analysis revealed that day +100 AMC (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.07-0.73, P=0.01) and mild chronic GVHD (RR 0.09, 95% CI 0.005-0.43, P=0.008) were independently associated with survival. To explore whether the patterns of lymphocyte and monocyte recovery had a prognostic value, we performed unsupervised hierarchical clustering on the studied hematopoietic parameters and identified three patient clusters, A-C. Patient clusters A and B both had improved OS compared with cluster C (77.8 months vs not reached vs 22.3 months, respectively, P<0.001). No patient in cluster C had a day +100 AMC >300. Both severe acute GVHD and relapse occurred more frequently in cluster C. Our data suggest that patients with low AMC by day +100 post fludarabine/melphalan-conditioned allogeneic hematopoietic SCT may be at risk for poor outcomes.

Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.

Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1-10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35-82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1-10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.

Low risk of symptomatic venous thromboembolic events during growth factor administration for PBSC mobilization.

The use of erythropoietic agents has been associated with an increased risk of venous thromboembolic events (VTEs), especially in patients with underlying malignancies. However, it is not known whether there is an increased risk of VTE associated with granulocyte growth factors. We reviewed 621 patients undergoing PBSC mobilization using granulocyte growth factors, alone or in combination with CY. Patients with a diagnosis of AL amyloidosis (AL: 114; 18%), multiple myeloma (MM: 278; 44%) Hodgkin lymphoma (HL: 20; 3%) or non-Hodgkin lymphoma (NHL: 209; 33%) were included. Symptomatic VTE occurred in six (0.97%) patients: two AL, two MM and two NHL. Of the six patients, two had pulmonary embolism, one developed deep vein thrombosis and three developed symptomatic catheter related thrombosis. Two patients with AL had heparin-induced thrombocytopenia and thrombosis. We found a low incidence of VTE among patients undergoing PBSC mobilization.

The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia.

A paucity of research exists examining the potential impact of tobacco use on cancer treatment outcomes, especially among patients treated with hematopoietic SCT (HSCT). A retrospective cohort study design was used to examine the impact of smoking on duration of hospitalization and overall survival among 148 consecutive patients undergoing HSCT for treatment of acute leukemia from 1999 to 2005. Of the 148 patients, 15% reported current smoking, 30% former smoking, and 55% never used tobacco. Patients were followed for a median 3.5 years (interquartile range=2.1-5.5). Compared to no history of smoking, current smoking was associated with worse pre-HSCT pulmonary function tests (P<0.02 in each case), more days hospitalization (46.2 days versus 25.7 days, P=0.025), and poorer overall survival (hazard ratio (HR)=1.88; 95% CI 1.09-3.25). Results were similar after multivariate adjustment, although the association with overall survival attenuated slightly (HR=1.75; 95% CI 1.00-3.06). Current smoking appears to adversely affect the number of days hospitalized post HSCT and overall survival. Translational research focused on interventions to promote tobacco cessation may lead to improved HSCT outcomes.

A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma.

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

Lymphopenia assessed during routine follow-up after immunochemotherapy (R-CHOP) is a risk factor for predicting relapse in patients with diffuse large B-cell lymphoma.

A specific predictor during routine follow-up to ascertain risk for relapse after standard chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified. Thus, we studied absolute lymphocyte count (ALC) as a marker of poststandard chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone (R-CHOP)) NHL relapse in patients with diffuse large B-cell lymphoma (DLBCL). ALC was obtained at the time of confirmed relapse and at last follow-up. From 2000 until 2006, 149 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP and followed up at Mayo Clinic, Rochester, were included in this study. Patients at last follow-up without relapse (N=112) had a higher ALC compared with those with relapsed lymphoma ((N=37) median ALC x 10(9)/l of 1.43 (range: 0.33-4.0) versus 0.67 (range: 0.18-1.98), P<0.0001, respectively). ALC at the time of confirmed relapse was a strong predictor for relapse with an area under the curve =0.91 (P<0.0001). An ALC <0.96 x 10(9)/l at the time of confirmed relapse had a positive predictive value of 72% and a positive likelihood ratio of 7.4 to predict relapse after R-CHOP in DLBCL. Patients with an ALC>or=0.96 x 10(9)/l (N=103) had a cumulative incidence of relapse of 6 versus 79% with an ALC <0.96 x 10(9)/l (N=46) (P<0.0001). This study suggests that lymphopenia measured by ALC can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard chemotherapy.

CD34+ cell dose and establishment of full donor chimerism at day +100 are important factors for survival with reduced-intensity conditioning with fludarabine and melphalan before allogeneic hematopoietic SCT for hematologic malignancies.

The combination of fludarabine and melphalan as a reduced-intensity conditioning (RIC) regimen extends allogeneic hematopoietic SCT (HSCT) as a therapeutic option for elderly or frail patients with relapsed, refractory or other high-risk hematologic malignancies. Whether any modifiable factors exist that could improve survival before or immediately after HSCT is unknown. We reviewed the medical records of the first 50 patients at our institution to undergo fludarabine/melphalan RIC from September 2000 to September 2007 to determine factors associated with survival. A total of 25 (50%) patients had undergone prior HSCT and as such was a high-risk group of patients. On multivariate analysis, CD34(+) cell dose greater than 5.5 × 10(6) per kg (risk ratio (RR) 0.44, 95% CI 0.19-0.98, P=0.02) and full donor chimerism at day +100 (RR 0.17, 95% CI 0.06-0.64, P=0.002) remained independent prognostic factors. In our series, achievement of full donor chimerism at day +100 was associated with an approximately 70% 2-year survival, a favorable outcome in this high-risk group of patients. Although the infused CD34(+) cell dose is a modifiable variable, whether donor lymphocyte infusions or other immunologic interventions should be performed to promote the establishment of full chimerism early post transplant remains unknown.

Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma.

We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.