Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia.

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia.

Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (cll), who typically have increased susceptibility because of hypogammaglobulinemia (hgg) related to their disease and its treatment. Immunoglobulin replacement therapy (igrt) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with hgg or a history of infection, or both. However, use of igrt in cll is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the hgg inherent to the disease. Thus, the utility of igrt has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of igrt in cll and provide a practical approach to its use in the prevention and management of infections.

Does adjuvant alpha-interferon improve outcome when combined with total skin irradiation for mycosis fungoides?

BACKGROUND: Patients with mycosis fungoides (MF) experience frequent disease recurrences following total skin electron irradiation (TSEI) and may benefit from adjuvant therapy. OBJECTIVES: To review the McGill experience with adjuvant alpha-interferon (IFN) in the treatment of MF. METHODS: From 1990 to 2000, 50 patients with MF were treated with TSEI: 31 with TSEI alone and 19 with TSEI + IFN. Median TSEI dose was 35 Gy. In the TSEI + IFN group, IFN was given subcutaneously at 3 x 10(6) units three times per week starting 2 weeks prior to start of TSEI, continued concurrently with the radiation and for an additional 12 months following TSEI. The TSEI alone group included 16 men and 15 women with a median age of 61 years (range 31-84). The TSEI + IFN group included 14 men and five women with a median age of 51 years (range 24-83). Clinical stage was IA, IB, IIA, IIB, III and IVA in 2, 9, 4, 8, 1 and 7 patients of the TSEI group and 0, 3, 3, 7, 4 and 2 patients of the TSEI + IFN group. RESULTS: Median follow up for living patients was 70 months. All patients responded to treatment. Complete response (CR) rate was 65% following TSEI and 58% following TSEI + IFN (P = 0.6). Median overall survival (OS) was 61 months following TSEI and 38 months following TSEI + IFN (P = 0.4). Acute grade II-III dermatitis was seen in all patients. Fever, chills or myalgia were seen in 32% of patients treated with TSEI + IFN. CONCLUSIONS: Concurrent IFN and TSEI is feasible, with acceptable toxicity. Even when controlling for disease stage, the addition of IFN did not appear to increase CR rate, disease-free survival or OS.

An epidemiological review of red cell transfusions in cancer chemotherapy.

OBJECTIVE: The objective of this chart review was to determine the frequency of transfusion and prevalence of anemia (hemoglobin result < 100 g/L) in patients receiving chemotherapy. DESIGN: This study was a retrospective review of medical charts. SETTING: Patients receiving chemotherapy were included from 12 tertiary care comprehensive cancer centres across Canada. MAIN OUTCOME MEASURE: The primary study outcome measure was red blood cell transfusion rate, controlling for patient variables. RESULTS: The 616 patients included had started chemotherapy in January-June 1992. For each subject, data collection finished 4 weeks after the end of the first regimen or after a maximum follow-up period of 26 weeks. Seventy-two patients (12%; 95% confidence interval 9.5% to 14.5%) were transfused for anemia (reasons other than blood loss), and 28% (95% confidence interval 24.5% to 31.5%) of the subjects were anemic during treatment. The univariate analyses of transfusion for anemia yielded significant associations with prognostic factors. In the multivariate analyses, platinum (odds ratio [OR] = 6.69) and anthracycline (OR = 3.56) chemotherapy, baseline hemoglobin (OR = 0.96) and disease stage (OR = 1.72) were statistically significant contributors. CONCLUSION: In this patient cohort, red blood cell transfusion was infrequent (12%). However, patient groups at high risk of transfusion could be identified, with platinum-based chemotherapy being the most significant contributing factor. The information obtained from this multicentre study may prove helpful in developing supportive care guidelines for the management of chemotherapy-related anemia requiring transfusion.

Mitotic separation of daughter cells in the human lymphoma B cell line Daudi involves L-selectin engagement and shedding.

BACKGROUND AND OBJECTIVE: A novel role for shedding of the surface molecule L-selectin has been proposed as an adjunctive phenomenon during cell detachment from marrow stroma or vessel endothelium. We wished to examine whether variations in expression of L-selectin on a lymphoma B cell line were linked to shedding. DESIGN AND METHODS: Mapping of L-selectin expression on the surface of Daudi lymphoma cells was performed by flow cytometry, fluorescence microscopy, and electron microscopy. Levels of shed L-selectin were evaluated by Western blotting of culture supernatants. Evaluation of cell cycle and proliferative activity was performed by flow cytometry. RESULTS: Large Daudi cells in S+G(2)/M phases were L-selectin positive, whereas small Daudi cells in G(0)/G(1) phase were L-selectin negative. During mitosis, L-selectin was distributed along the cleavage furrow, and gradually lost. Electron microscopy revealed that separating Daudi cells were negative for L-selectin on the entire surface, except minute aggregates of L-selectin within the cleavage furrow. Addition of agents known to interfere with the ligand-binding portion of L-selectin (sulfatides, MoAbs: Lam1.3 and TQ1) results in loss of L-selectin. Removal of L-selectin by digestion with chymotrypsin inhibits Daudi proliferation. The MoAb FMC46 did not interfere with proliferation. Proliferating Daudi cells produced large quantities of shed L-selectin. Inhibition of Daudi proliferation resulted in levels of shed L-selectin below the limit of detection. INTERPRETATION AND CONCLUSIONS: L-selectin is re-distributed on the cell surface of Daudi cells during the last phase of mitosis, in which plasma membrane invagination occurs between newly formed daughter cells. Shedding of L-selectin is involved in the cytokinesis of Daudi cells.

Iron absorption and therapy after gastric bypass.

BACKGROUND: Iron deficiency anemia is a common complication of gastric bypass. The authors assessed the value of taking vitamin C with oral iron in correcting deficiencies in iron stores and anemia postoperatively. MATERIALS AND METHODS: Iron absorption tests were performed on 55 patients 3.2+/-2.0 years after isolated gastric bypass to identify those at higher risk for the late development of anemia. Twenty-nine of this group agreed to a therapeutic trial of iron alone or with vitamin C over a 2-month period. All 55 patients were followed up for 27.1+/-1.0 months following the study. RESULTS: The iron absorption test identified patients with low iron stores, as indicated by low serum ferritin, and those with sufficient absorption surface to benefit from oral iron. The addition of vitamin C appears to enhance the therapeutic effect of iron by correcting ferritin deficits (P < 0.01) and anemia (P < 0.05). Differences in intestine length bypassed by the operation (10 vs. 100 cm) did not affect late ferritin and hemoglobin values. CONCLUSION: This study suggests but does not prove that the addition of vitamin C to iron therapy after gastric bypass is more effective in restoring ferritin and hemoglobin than iron alone. These results are in contrast with the outcome 22.8 months later, when approximately 50% of study patients were again anemic. Closer follow-up of patients is urgently needed.

Interferon in the Treatment of Multiple Myeloma.

BACKGROUND: The role of interferon (IFN) in the treatment of multiple myeloma has been investigated for nearly two decades. The mechanisms underlying antitumor activity of IFN may be mediated by antiproliferative and immunomodulatory effects. The benefits of treatment remain controversial, and guidelines for the use of IFN in myeloma are needed. This review evaluates available data on the impact of IFN therapy on multiple myeloma. METHODS: A MEDLINE search of published prospective, randomized trials of IFN in multiple myeloma provided the data included in this review, as well as selected abstracts presented at international meetings. RESULTS: IFN has complex and pleiotropic effects on human myeloma lines and ex vivo myeloma cells. An antiproliferative effect with disruption of the IL-6-mediated growth loop may be crucial, but biologic heterogeneity in myeloma may have important clinical implications for response to IFN. IFN has demonstrable antitumor activity in multiple myeloma but appears to have a modest effect on overall survival when combined with chemotherapy during induction or when used as maintenance therapy. Most studies have shown a prolongation of the plateau phase of disease with IFN of variable duration of between four and 12 months. CONCLUSIONS: A reliable estimate of the benefit of IFN in the overall population of patients with myeloma is difficult to determine with discordant results from different trials. Possible sources of heterogeneity in randomized trials need to be identified, and recognition of subsets of patients who may benefit is important. Cost-benefit analyses with integration of quality-of-life data are essential for developing guidelines for the use of IFN in myeloma.

Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group.

PURPOSE: This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. RESULTS: Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). CONCLUSION: MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.

Expression of the human NRAMP1 gene in professional primary phagocytes: studies in blood cells and in HL-60 promyelocytic leukemia.

In the mouse, mutations at the natural resistance-associated macrophage protein 1 (Nramp1) gene abrogate resistance to infection with antigenically unrelated intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Nramp1 expression is restricted to reticuloendothelial organs and peripheral blood leukocytes, where the protein may function as a membrane transporter of an as yet to be identified substrate. To identify the human blood cell type(s) expressing NRAMP1 mRNA and determine how Nramp1 expression is regulated in these cells, we have examined separated populations of peripheral blood leukocytes and in vitro cell lines. We observed that polymorphonuclear leukocytes (PMN) are the major site of NRAMP1 expression, followed to a lesser degree by monocytes (MN). Migration of MN to tissues (alveolar macrophages) or maturation in vitro (long-term culture) was associated with a higher level of NRAMP1 expression compared with blood MN. Northern analyses of RNA from model cultured cells showed absence of NRAMP1 expression in transformed cell lines from either erythroid or lymphoid T or B lineages as well as progenitors of the monocyte/macrophage pathway (KG1, U937, THP1), and the HL-60 promyelocytic leukemia. Induction of differentiation of HL-60 cells toward either the monocyte/macrophage (vitamin D3, phorbol ester) or the granulocyte pathways (DMF, DMSO), as measured by induction of IL8-Rb, c-FMS, and CD14 marker gene expression, was concomitant with a strong induction of NRAMP1 expression. These results suggest that NRAMP1 expression is specific to the myeloid lineage and is acquired during the maturation of PMN and MN. The possibility that NRAMP1 may be a component of the phagosomal/endosomal apparatus common to PMN and MN is discussed.

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD).

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Rheumatic disease patients, prone to Sjögren's syndrome and/or lymphoma, mount an antibody response to BHRF1, the Epstein-Barr viral homologue of BCL-2.

The IgG response to Epstein-Barr virus (EBV) early antigens [BHRF1 (p 17.1), the viral homologue of bcl-2, and BMRF1 (p50.10), a DNA binding protein] was measured in patients with rheumatic disease to see whether there was any association with lymphoma. Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatic disease patients with lymphoma, patients with lymphoma who did not have a rheumatic disease and normal individuals were tested for the presence of anti-EA peptide antibodies by ELISA. Whereas antibodies to early EBV peptides were detected only in one normal individual, patients with rheumatic diseases, especially those with either SS and/or lymphoma, had a much higher frequency of antibody detection. Antibodies to BMRF1 p50.10 were found in 7-50% of patients, and to BHRF1 p17.1 in 4-27%, depending on the group studied. Patients with lymphoma lacking a rheumatic disease had a 2-fold lower frequency of anti-BHRF1 antibodies, compared to the lymphoma plus rheumatic disease group. The increased immune response to the EBV EA proteins in the rheumatic diseases probably reflects the presence of reactivated virus, and the BHRF1 protein (the viral homologue to bcl-2) could, via inhibiting apoptosis, contribute to the lymphoproliferative nature of these diseases.

Parathyroid-hormone-related peptide in hematologic malignancies.

PURPOSE: To determine whether parathyroid-hormone-related peptide (PTHRP) is an important pathogenetic mediator of hypercalcemia in patients with hematologic malignancies. PATIENTS AND METHODS: We conducted a cohort analytic study in 76 consecutive patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease, multiple myeloma, and Waldenstrom's macroglobulinemia, 14 of which were hypercalcemic. Thirty normal subjects served as a control group. RESULTS: Using the NH2 -terminal radioimmunoassay, PTHRP concentrations in heavy controls were undetectable (<7.5 pmol equivalents of PTHRP [fragment 1-34] per liter). The majority of hypercalcemic patients (8/14) had non-Hodgkin's lymphoma, and 62.5% of these (5/8) had significant elevations of circulating PTHRP concentrations (mean 70.5 +/- 38.5 pmol equivalents of PTHRP per liter) (P <0.01). In non-Hodgkin's lymphoma, 11 of 30 patients with advanced disease (stage IV) had elevated PTHRP concentrations, and of these, 8 of 11 had high-grade pathology. In contrast, only 3 or 21 patients with less advanced disease (stage I to III) had elevated PTHRP concentrations. In 4 NHL patients with less advance PTHRP concentrations sampled prior to cytotoxic chemotherapy, tumor response was associated with a decrease in PTHRP. Concomitant suppression of 1,25(OH)2D3 concentrations was observed in 66% of hypercalcemic patients with non-Hodgkin's lymphoma. CONCLUSIONS: These results suggest that PTHRP may be an important pathogenetic factor in the development of hypercalcemia in hematologic malignancies, notably in non-Hodgkin's lymphoma.

A solitary plasmacytoma of donor origin arising 14 years after kidney allotransplantation.

Allotransplantation of solid organs transfers passenger leucocytes which may give rise to a state of persistent microchimaerism. In this report we describe the case of a patient who developed a solitary plasmacytoma in a transplanted kidney more than 10 years after allografting. The diagnosis was established on the basis of the presence of a monoclonal IgG kappa peak in the serum, and light chain proteinuria, the plasmacytoid features of tumour cells including cell surface expression of IgG, kappa light chains, CD20, CD38 and CD56, the absence of lytic bone lesions and a normal bone marrow biopsy, and the disappearance of the monoclonal IgG peak after graft nephrectomy. A donor origin of the tumour was established by HLA DNA typing of tumour, tumour-free kidney tissue, and peripheral blood leucocytes, respectively.

Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone. PATIENTS AND METHODS: In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors. RESULTS: Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment. CONCLUSION: Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

Non-Hodgkin's lymphoma of the spleen.

Although the spleen is frequently involved in disseminated non-Hodgkin's lymphoma (NHL), splenic presentation as the initial or only site of disease is uncommon. The true incidence of splenic lymphoma is difficult to estimate because of the variable definition of this disease, however, the diagnosis of primary lymphoma of the spleen should be limited to involvement of only the spleen and splenic hilum. Using this restricted definition, our experience suggests that the prognosis of NHL of the spleen, when pathologically staged, may have a favorable prognosis which approximates that seen with limited stage NHL at other sites. The influence of pathologic subtype on natural history and the impact of adjuvant therapy are discussed.

Graffi murine leukemia virus: molecular cloning and characterization of the myeloid leukemia-inducing agent.

The Graffi murine leukemia virus (MuLV) is a retroviral mixture that induces predominantly myeloid leukemia in several inbred strains of mice. To analyze the viral component responsible for the myeloid leukemogenesis, we cloned several proviruses from a Graffi MuLV-infected cell line. Several infectious molecular clones were obtained that could be classified into two distinct groups of infectious MuLV. Both types of MuLV were nondefective, ecotropic, and NB tropic and induced granulocytic leukemia in BALB/c and NFS mice. Restriction enzyme analysis and molecular hybridization with several MuLV probes on one molecular clone from each group revealed that both groups are closely related to each other but are clearly distinct from all known retroviruses. One component of MuLV, however, induced leukemia with a shorter latency period and harbored a lengthier long terminal repeat. The long terminal repeat of the more leukemogenic component of MuLV had acquired a 60-bp perfect duplication in the U3 region. Analysis of the tumor DNAs with probes for the mouse T-cell receptor and immunoglobulin heavy chain genes revealed frequent rearrangements with one or both probes. This concomitant expression by leukemic cells of markers of different lineages, observed in human leukemias, has been termed "lineage infidelity" and confirms that the latter rearrangements are not restricted to hematopoietic precursors committed to lymphoid differentiation.