One hundred and eighteen patients presenting with high-grade non-Hodgkin's lymphoma, undergoing autologous bone marrow transplantation (ABMT) in first complete remission (CR), have been reported to ...the European Group for Bone Marrow Transplantation (EBMT). Of these, 102 were eligible for inclusion in this study following review of registration forms. Patients with lymphoblastic lymphoma were excluded. Remission induction and high-dose regimens varied between contributing centres. A maintained CR was observed in 90% of patients. Early relapse was observed in 6%, and 4% suffered toxic deaths. With a median follow-up of 45 months (3–112 months), the 5-year actuarial overall and pro-gression-free survivals are both 70%. Nineteen (18%) patients relapsed at a median of 3.5 months (0.25–52 months) after ABMT, only 1 achieving a further durable CR. The only factor with prognostic significance was histological subtype, with diffuse small noncleaved-cell lymphoma having a significantly worse outcome. High-dose therapy and ABMT has produced effective consolidation of first remission in this group of patients, even in those with poor prognostic features at presentation.
High response and overall survival rates have been reported for second- and third-generation combination chemotherapy regimens used in the treatment of advanced intermediate- and high-grade ...non-Hodgkin's lymphoma (NHL). Results with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy have been particularly impressive, although this regimen produces considerable toxicity. We have devised a similar regimen, which differs from previously reported weekly regimens in that it includes etoposide given at 14-day intervals. The doses of methotrexate and prednisolone were lower in our regimen than those used in MACOP-B. Alternating cycles of cyclophosphamide, doxorubicin, and etoposide (week 1) and methotrexate, bleomycin, and vincristine (week 2) were given for a total of 12 weeks, with continuous oral prednisolone and prophylactic antibiotics. We report here the first 61 patients entered onto this study. The overall response rate is 84% (57% complete remission CR, 27% partial remission PR). With a median follow-up of 32 months for surviving patients, the actuarial overall survival at 3 years is 47%, and the failure-free survival is 45%. The dose-limiting toxicity of this regimen was mucositis. Five deaths occurred during chemotherapy, two of which were due to sepsis. The dose intensities of cyclophosphamide and doxorubicin in this regimen are considerably lower than those in MACOP-B. However, because of the inclusion of etoposide, the projected average relative dose intensity for our regimen is higher than that for MACOP-B. Our regimen has produced inferior results to those reported for MACOP-B. This may be because the addition of etoposide has failed to compensate for the lower doses of doxorubicin and cyclophosphamide. Alternatively, it may reflect differences in the presenting features of the patient populations.
Background: Patients with advanced Hodgkin's disease failing to achieve complete remission with chemotherapy or developing disease progression within 1 year have a poor prognosis with salvage ...chemotherapy. Patients and methods: Twenty-five patients fulfilling the above criteria after failing treatment with ChlVPP (chloram-bucil, vinblastine, procarbazine and prednisolone) or its variant were treated with a new salvage regimen CAPE/PALE (cyclophosphamide, adriamycin, prednisolone, etoposideand lomustine), given for 6 courses at three weekly intervals. Results: Thirteen of the 25 patients (52%) achieved complete remission. After a minimum foliow-up period of 38 months five of these patients remained free from disease progression. This regimen was very well tolerated. Conclusions: CAPE/PALE produces results comparable to other salvage regimens in Hodgkin's disease. New strategies are however required for this patient group.
Summary
Autologous stem cell transplantation (ASCT) with cyclophosphamide, etoposide and oral busulfan (BuCyVP) is an effective therapy for relapsed or refractory non‐Hodgkin lymphoma (NHL). ...Substituting intravenous for oral busulfan reduces variability in drug exposure, potentially improving the safety and efficacy of the BuCyVP regimen. We retrospectively compared the outcomes of 604 consecutively treated patients who underwent ASCT for NHL with BuCyVP using oral (n = 468) or IV (n = 136) busulfan, without measurement of busulfan levels for pharmacokinetic (PK) analysis. Patients who received oral busulfan experienced more severe oral mucositis and a higher incidence of nonrelapse mortality. Median overall survival (OS) after ASCT was 72 months with oral busulfan but was not reached for the IV busulfan group. IV busulfan was associated with a lower rate of relapse, and superior relapse‐free survival (RFS) and OS. In multivariate models, the route of busulfan administration was an independent prognostic factor for relapse (P = 0·01), RFS (P = 0·002) and OS (P = 0·001). IV busulfan appears to provide better efficacy and lower toxicity than oral busulfan in ASCT with BuCyVP for NHL. Whether PK‐based busulfan dosing can achieve further improvements in this setting is worthy of study.
Six cases of metastatic germ cell tumors of the testis involving the gastrointestinal (GI) tract are reported. Three cases were primary seminomas, and three were nonseminomatous. All six cases ...involved the upper GI tract, three occurring at presentation and three at relapse, with a disease‐free interval of 3 months to 10 years. Isolated GI involvement did not occur. The presumed mode of spread was by haematogenous dissemination in three and direct extension from paraaortic lymph nodes in three. Symptoms suggestive of involvement were severe abdominal pain secondary to high intestinal obstruction or mucosal ulceration, severe lumbar pain, and symptoms of anemia as a result of clinically evident or occult blood loss. Four patients were now disease‐free after chemotherapy, one died of an unrelated illness, and one patient was receiving treatment for relapsing disease.
Introduction: A network of cytokines and chemokines exists in HL that maintains a favorable tissue microenvironment. Serum levels of cytokines and chemokines have been examined as potential ...biomarkers of response and prognosis. TARC (CCL17) and MDC (CCL22) are produced by Hodgkin cells, attract Treg and Th2 cells, and have been associated with advanced stage of disease and inferior response. IL10, a pleiotropic cytokine produced by Tregs and Hodgkin cells fosters an immune suppressive environment by inhibiting Th1 cells and has been associated with unfavorable outcome in HL. CD163 is present in anti-inflammatory M2 tumor associated macrophages, and soluble CD163 (sCD163) levels have also been associated with tumor burden and response during HL therapy. We sought to identify prognostic serum markers alone and in combination with PET in a recent large prospective study of untreated HL.
Methods: S0816 was a US intergroup phase 2, risk adapted trial for stage III/IV untreated HL where patients (pts) received doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy for 2 cycles. Based on interim PET after cycle 2 (PET2), pts received escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (eBEACOPP) x 6 (if PET2 positive) or ABVD x 4 (total 6, if PET2-negative). Pts also received a PET scan at the end of therapy (PET3). We examined serum levels of TARC, MDC, IL10 and sCD163 and correlated these with PET results and progression free survival (PFS) and overall survival (OS). Pts who provided informed consent to participate had planned serum samples drawn at baseline (pretherapy), after cycle 2, and at completion of therapy. Serum samples were frozen locally and tested centrally (ALLIANCE Molecular Reference Laboratory) by enzyme-linked immunosorbent assay (R&D systems, Minneapolis MN). Statistical analysis was performed at the SWOG statistical center. All statistical analyses report unadjusted p-value across the four serum markers.
Results: 559 samples from an initial 236 pts were available for study (236 baseline, 166 post cycle 2, and 157 post-therapy samples). The clinical features (age, stage, presence bulk disease, presence B symptoms, and international prognostic scores (IPS)) were similar between the 236 pts and the overall trial cohort. Elevated levels of the 4 markers were seen at diagnosis with rapid declines after cycle 2 and at completion of therapy. For PET results, univariate landmark Cox regression showed that PET2 correlated with OS (HR 3.4, 95% confidence interval (CI) 1.14 - 10.27, P=.028) and PET3 strongly correlated with both PFS and OS (HR 9.0 and 7.7, 95% CI 5.10-15.98 and 2.17-27.40, P<.0001 and P=.0016, respectively). Univariable analysis of baseline levels of the 4 markers showed no association with PFS or OS. Post-cycle 2 levels of sCD163, adjusting for PET2 result, showed association with PFS (HR 0.5, 95% CI 0.34 - 0.90, P=0.017), but other markers at this time point showed no association with survival. A landmark analysis of elevated post therapy levels of IL10, adjusting for PET3 result, were associated with both inferior PFS and OS (HR 1.6 and 2.3, 95% CI 1.25-2.06 and 1.50-3.53, P=.0002 and P=.0001, respectively, Figure 1). Post therapy TARC was also associated with PFS (HR 1.4, 95% CI 1.07-1.84, P=0.015). We also examined the change in serum markers over time in conjunction with PET response (baseline to post cycle2 and post-therapy) for association with survival. Only sCD163 impacted PFS in multivariable modeling adjusting for PET3 results (HR 0.6, 95% CI 0.37-89, P=0.012).
Conclusions: We evaluated serum levels for IL10, sCD30, TARC and MDC in the setting of a PET-directed regimen in advanced-stage HL. Baseline serum levels were not prognostic, but IL10 levels after therapy were associated with PFS and OS. sCD163 may provide additional prognostic information. Collectively, IL10 and sCD163 are worthy of further investigation. Given the promise of immune checkpoint inhibitors, IL10 and its immunosuppressive properties may be of particular interest in regimens containing these therapeutic agents.
Support: NIH/NCI grants CA180888, CA180819, CA180821, and CA180820.
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Hsi:Abbvie: Research Funding; Eli Lilly and Co.: Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Cellerant Therapeutics: Research Funding. Evens:Seattle Genetics: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Affimed: Consultancy; AbbVie: Consultancy; • Spectrum Pharmaceuticals: Consultancy; Millennium: Consultancy; Merck: Consultancy. Straus:Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Bartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Sweetenham:Seattle Genetics: Consultancy, Honoraria. Barr:Seattle Genetics: Consultancy; Infinity: Consultancy; Novartis: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Fanale:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; ONYX: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; GENENTECH: Research Funding; ONYX: Research Funding; GENENTECH: Research Funding; TAKEDA: Honoraria, Research Funding; ADC THERAPEUTICS: Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees. Kahl:Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy; Genentech: Consultancy. Leonard:Celgene: Consultancy, Research Funding; Roche: Consultancy. Friedberg:Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy.
Investigations of VH gene mutational patterns in B-cell tumors are often performed at an arbitrary time point of disease. To assess the effects of disease progression, tumor-derived VHgenes have been ...monitored from presentation through treatment and relapse in one patient with follicle center lymphoma (FCL), and two patients with primary diffuse large B-cell lymphoma (DLCL). The patient with FCL and one patient with DLCL both achieved clinical remission, although this was only partial in the FCL. However, both subsequently relapsed, and the second patient with DLCL was refractory to radiotherapy and chemotherapy. In each case, the tumor-derived VH sequence was identified, and the CDR3 “clonal signature” was used to track tumor cell sequences in subsequent biopsies. All cases showed somatic mutations, with intraclonal heterogeneity evident at presentation, and some sequences were aberrant. The VH sequences of the DLCL which responded to treatment became homogeneous at relapse. The sequences of both the FCL and the refractory DLCL remained heterogeneous. In all cases, transcripts of multiple Ig isotypes could be identified, and there was immunophenotypic evidence for expression of several Ig isotypes. The case of refractory DLCL had identifiable transcripts from IgM, IgD, IgA, IgG, and IgE, but appeared to lose the ability to produce alternative isotype transcripts and protein at the late stage of disease. These cases indicate that VH gene analysis can be used to probe tumor cell behavior in cases of lymphoma and that perturbations caused by therapy and disease progression can occur.
We have assessed the potential use of the mononuclear cell (MNC) content as the sole assessment of graft quality in 35 patients receiving BEAM (carmustine, etoposide, cytosine arabinoside, melphalan) ...chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation for malignant lymphoma. PBPCs were mobilized with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), and each patient underwent two (n = 20) or three (n = 15) apheresis procedures. Median cell yields were 5.08 x 10(8) MNC/kg (range 1.59-15.70 x 10(8)) and 73.10 x 10(4) CFU-GM/kg (range 0.09-346.72 x 10(4)). All patients achieved hematologic recovery. Median days to neutrophils > or = 0.1 x 10(9)/L, neutrophils > or = 0.5 x 10(9)/L, and platelets > or = 25 x 10(9)/L were 11 (range 8-15), 13 (range 10-37), and 11 (range 7-41), respectively. A close correlation was observed between the MNC and CFU-GM dose (r = 0.79, p < 0.0001). We have previously defined a minimum threshold CFU-GM dose of 20 x 10(4)/kg for patients undergoing high-dose therapy. This corresponds with an MNC dose of 3 x 10(8)/kg. Comparison of engraftment in patients receiving 3 x 10(8) MNC/kg with those receiving lower doses demonstrated significantly longer times to recovery of neutrophils to > or = 0.5 x 10(9)/L and platelets to > or = 25 x 10(9)/L. All patients receiving an MNC dose of > or = 3 x 10(8)/kg achieved neutrophil and platelet recovery by days 12 and 24, respectively. These preliminary data demonstrate that for patients with lymphoma undergoing PBPC mobilization according to this protocol and treatment with BEAM chemotherapy, assessment of MNC dose alone is sufficient to predict early hematologic recovery. Additional assays such as CFU-GM or CD34+ cell counts may not be necessary if this MNC dose is reinfused.
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