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News Article | July 10, 2017
Site: www.eurekalert.org

Three case reports published in the New England Journal of Medicine demonstrate the promise of cancer immunotherapy in gray zone lymphoma, a rare subtype that mixes characteristics of Hodgkin and Non-Hodgkin forms of the disease. In one case from the University of Colorado Cancer Center using nivolumab and two from the National Institutes of Health using pembrolizumab, treatment with immune therapy "checkpoint inhibitors" followed unsuccessful therapies and was based on clinicians' ability to match the mechanism of the drug with the known molecular alterations in this lymphoma. These three cases represent the first successful uses of immune therapies in gray zone lymphoma, potentially paving the way for clinical trials utilizing this strategy in this and related conditions. "For me, trying nivolumab was a binary choice: I could try the drug or I could give up," says Bobbie Flexer, PhD, the patient treated at CU Cancer Center. Flexer, a retired mathematics education professor from CU Boulder, had not improved after multiple rounds of chemotherapy and radiation therapy. Genetic testing of Flexer's tissue showed focal over-expression of the protein PD-L1. This protein displayed on a tumor cell's surface acts as a white flag telling the immune system's T cells not to attack. Specifically, T-cells probe other cells with their own cell-surface protein, PD-1, and it is the interaction between PD-1 and PD-L1 that can disarm the immune system against a marked cell. A major strategy of cancer immunotherapy is to block this interaction between a T cell's PD-1 and a cancer cell's PD-L1. If one is blinded from seeing the other, the immune system can be reactivated to attack cancer cells. This is the strategy of nivolumab. It blocks PD-L1 from binding to PD-1 (it inhibits this checkpoint) thus removing the immune system's blinders to cancer. The drug is approved as a first-line therapy for metastatic melanoma and has also been used to treat non-small cell lung cancer, Hodgkin disease and renal cancer. It had not previously been used against gray zone lymphoma. "It was a leap of faith when we started the drug," says Flexer's oncologist, Manali Kamdar, MD, investigator at the CU Cancer Center and Clinical Director of Lymphoma Services at University of Colorado Hospital. Kamdar joined the Center in fall 2014 to establish the lymphoma program. She explains that there are about 100 different types of lymphoma, one of which is gray zone lymphoma. "It's so gray that no one knows how to spell it -- should it be an 'e' or an 'a' in gray?" Kamdar says. "This is true to the point that not every pathologist will even call it gray zone lymphoma. This highlights the importance of academic medical centers. If you have a diagnosis of a rare subtype of lymphoma, it is pertinent to get a second opinion at an academic medical center to avoid misdiagnosis." Chemotherapy is only effective in roughly 50 percent of grey zone lymphoma, due in part to the aggressive nature of the condition and in part to the difficulty of obtaining a correct diagnosis. "It should have a more striking, appalling name. 'Gray zone' sounds like it's a mild case of something or other," Flexer says. At the time of her diagnosis, Bobbie described herself as an "exercise addict," going to about four workout classes and walking with friends twice per week. Then, "I had a period of shortness of breath, a cold and suddenly I felt like I had pneumonia," she says. An x-ray showed fluid in her lungs, and after the procedure to remove this fluid, a nurse prepared Bobbie for discharge from the hospital, which included a routine test of blood level oxygen. When the test came back low, Bobbie changed from her street clothes back into a hospital gown. It was the start of a long process of diagnosis. The process of treatment has been even longer. Bobbie started with combination chemotherapy known as R-EPOCH, which includes an antibody therapy called rituximab along with chemotherapy consisting of etoposide, prednisone, vincristine (Oncovin) and doxorubicin hydrochloride. Unfortunately, after six cycles of the therapy, Bobbie's PET scan showed that her disease had progressed. "Given Bobbie's age and her resistance to chemotherapy it was difficult to simply increase her dose. Bobbie's tumor biopsy expressed a protein called CD30 and so we started her on brentuximab, which targets these CD30 cells," Kamdar says. The drug is one in a class of what are called "antibody-drug conjugates" in which an antibody is designed to seek a cell-surface protein, bringing along the payload of chemotherapy. In this way, brentuximab delivers chemotherapy more exclusively to cells marked by CD30. "Unfortunately Bobbie's disease progressed through multiple cycles of brentuximab. Subsequently we switched her to another combined chemotherapy, namely gemcitabine with oxaliplatin," Kamdar says. "It's a very old, very rough form of chemo. She looked like hell," says Bobbie's husband, Abe, a retired faculty member of the CU Boulder Department of Molecular, Cellular and Developmental Biology. Bobbie was not tolerating this latest attempt at chemotherapy. Besides another PET scan showed that it was doing little good. "At that point, I knew that one recommendation was, 'oh gosh, she's 80 years old, don't do anything.' But Dr. Kamdar is really on top of everything -- you can't breathe heavily and not have her look into something. Dr. Kamdar had to come up with something new," Bobbie says. That something new was nivolumab, which Bobbie and Dr. Kamdar hoped would unleash Bobbie's own immune system against her disease. "This was a new drug and Dr. Kamdar explained very thoroughly that it would be an off-label use. She made it clear there aren't a lot of data where I am," Bobbie says. "Still, she thought it might be worth a try. We went for it." "Within one dose, she was in less pain and she looked much better," Kamdar says. A PET scan after six doses showed that Bobbie's gray zone lymphoma was in complete remission. Of course, the treatment hasn't been without side-effects. "When they put you on a drug at the hospital, they tell you how it's supposed to act and they tell you all the side effects. They hand you a written sheet of what can go wrong. For nivolumab, they said think of every organ in your body - any one or more may become inflamed," Bobbie says. The goal of the drug is to cajole the immune system into specifically attacking a patient's cancer. But with brakes removed, the immune system may also attack other tissues that use PD-L1 to keep themselves safe. For Bobbie, this meant two bouts of pneumonitis, an inflammation resulting from her immune system's activation against her lungs. "They treated it successfully with a prednisone burst each time," Bobbie says. She also experienced an uptick in pancreas enzymes that caused high blood glucose levels. Bobbie is learning to treat that side-effect with insulin. And dietitians at University of Colorado Hospital helped her manage expected gut related side effects. Bobbie Flexer has now been on nivolumab for over half a year. To Kamdar, the case was striking enough to warrant submitting a report to the New England Journal of Medicine. Interestingly, the editor at the journal had just received two similar case reports from the National Institutes of Health, using the related immune therapy pembrolizumab to target the condition in a nearly identical way ("The idea had found its time," says Kamdar.") Alone, any one of these cases may not have earned publication; together they form a compelling picture of a new strategy to target gray zone lymphoma. "Now she's back on the drug and doing fairly well, in complete remission," says Kamdar. "In addition to being fortunate enough to have the excellent facilities at the CU Cancer Center and UCHealth Bone Marrow Transplant Center available to me, I was lucky enough to have a very bright, knowledgeable, and caring oncologist who was not willing to give up on someone who was 80 and presenting with a very bad diagnosis," Bobbie says. "I was also fortunate that my husband saw his role as a partner in this long and complicated project and took on the tasks of primary caregiver and medical researcher. Our daughters and granddaughter have been huge supports, flying in to Colorado from each coast regularly. Finally, our extended family and friends have been terrific, willing to ride the roller coaster with us." These three cases demonstrate the ability of knowledgeable clinicians to infer rational treatments based on the genetic specifics of a patient's disease. The cases also show the potential for new, genetically-targeted medicines to transcend the disease for which they were developed. Seeing gray zone lymphoma not only as a cancer of the lymph nodes, but as one in a larger class of cancers dependent on use of the protein PD-L1 to evade the immune system allowed Manali Kamdar to match the right patient with the right drug, and now allows Bobbie Flexer extra months and even years of life.


Musso M.,Oncohematology and Bone Marrow Transplantation Unit La Maddalena | Scalone R.,Oncohematology and Bone Marrow Transplantation Unit La Maddalena | Marcacci G.,Italian National Cancer Institute | Lanza F.,University of Ferrara | And 6 more authors.
Bone Marrow Transplantation | Year: 2010

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkin's (n20) and non-Hodgkin's lymphoma (n64) were conditioned with a FEAM regimen (FTM 150 mg/m 2 on days -7, -6, etoposide 200 mg/m 2 and cytarabine 400 mg/m 2 on days -5, -4, -3, -2 and melphalan 140 mg/m 2 on day -1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (500 × 10 9 /l) and plt (20 000 × 10 9 /l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety. © 2010 Macmillan Publishers Limited All rights reserved.


Girmenia C.,University of Rome La Sapienza | Raiola A.M.,University of Genoa | Piciocchi A.,GIMEMA Foundation | Algarotti A.,Azienda Ospedaliera Papa Giovanni XXIII | And 37 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs. © 2014 American Society for Blood and Marrow Transplantation.


Louw V.J.,University of the Free State | Bassa F.,Stellenbosch University | Chan S.W.,University of Witwatersrand | Dreosti L.,University of Pretoria | And 16 more authors.
South African Medical Journal | Year: 2011

Introduction. Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal haematopoietic disorders characterised by chronic and progressive cytopenias resulting from ineffective haematopoiesis. Treatment is complicated by differences in disease mechanisms in different subgroups, variable clinical phenotypes and risk of progression to acute myeloid leukaemia. Rationale. Changes in disease classification, prognostic scoring systems, the availability of novel treatment options and the absence of South African guidelines for the diagnosis and management of these complex disorders underpinned the need for the development of these recommendations. Methods. These recommendations are based on the opinion of a number of experts in the field from the laboratory as well as clinical settings and came from both the private and institutional academic environments. The most recent literature as well as available guidelines from other countries were discussed and debated at a number of different meetings held over a 2-year period. Results. A comprehensive set of recommendations was developed focusing on risk stratification, supportive management and specific treatment. Novel agents and their indications are discussed and recommendations are made based on best available evidence and taking into account the availability of treatments in South Africa. Conclusion. Correct diagnosis, risk stratification and appropriate therapeutic choices are the cornerstones of success in the management of patients with MDS.


Rambaldi A.,Hematology and Bone Marrow Transplant Unit | Grassi A.,Hematology and Bone Marrow Transplant Unit | Masciulli A.,Fondazione Mario Negri Sud | Boschini C.,Hematology and Bone Marrow Transplant Unit | And 30 more authors.
The Lancet Oncology | Year: 2015

Background: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. Methods: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m2 per day for four consecutive days (from days -6 through -3; total dose 160 mg/m2). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. Findings: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). Interpretation: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Funding: Agenzia Italiana del Farmaco. © 2015 Elsevier Ltd.


PubMed | Transplant and Cellular Therapy Center, Hematology and Bone Marrow Transplant Unit, University of Pavia, University of Bari and 14 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2015

The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients.We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 08 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 128 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957.Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 275 months (IQR 98-443). 1-year non-relapse mortality was 172% (95% CI 116-254) in the busulfan plus cyclophosphamide group and 79% (43-143) in the busulfan plus fludarabine group (Grays test p=0026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event).In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients.Agenzia Italiana del Farmaco.


Kaeda J.,Medizinische Klinik m.S. Hamatologie und Onkologie | Bonamino M.,INCA | Ayres-Silva J.,INCA | Ayres-Silva J.,Bone Marrow Transplant Center | And 8 more authors.
Leukemia and Lymphoma | Year: 2014

Assessing the clinical significance of JAK2 V617F mutant allele burden is complicated by a myriad of techniques reported to detect and quantify the mutation. As a consequence, the level of sensitivity and how the data is reported vary. Harmonization of well-defined molecular studies would permit evaluation of the clinical significance of measuring allele burden and rapid determination of the efficacy of novel agents for the treatment of chronic myeloproliferative neoplasia via multicenter clinical trials, at the subclinical level. Here we report a comparison between the widely available TaqMan quantitative real time polymerase chain reaction (Q-PCR) and competitive PCR (C-PCR) assays. We found that the tumor load was invariably greater when measured by C-PCR compared to that recorded by Q-PCR. Furthermore, none of the samples converted from undetectable to detectable when the enriched granulocyte (GR) fraction was tested. While a difference in the V617F allele levels was detected between GR fraction and whole blood, this was not statistically significant. © 2013 Informa UK, Ltd.


Busca A.,Bone Marrow Transplant Center | Pecoraro C.,Hematology 2 | Giaccone L.,Bone Marrow Transplant Center | Bruno B.,Bone Marrow Transplant Center | And 12 more authors.
Leukemia and Lymphoma | Year: 2014

The aim of the present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplant between January 1995 and September 2010 in two Italian hematology centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 33% (95% confidence interval [CI] 21-45%) and 78% (95% CI 66-90%), respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (95% CI 6-21%). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (95% CI 31-51%) and 49% (95% CI 38-59%), respectively. On multivariate analysis, advanced disease stage at transplant was the major independent variable associated with an inferior 2-year PFS (HR 3.66, 95% CI 1.98-6.76) and OS (HR 3.68, 95% CI 1.95-6.93). Use of an alternative donor was an independent variable associated with TRM (HR 3.18, 95% CI 1.31-7.72). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to an improved outcome. © 2014 Informa UK, Ltd.


PubMed | Neonatal Intensive Therapy Unit, Infectious Disease Unit and Bone Marrow Transplant Center
Type: | Journal: Bone marrow transplantation | Year: 2016

The aim of this study was to investigate the methods of conception and delivery, as well as the course and outcome of 42 pregnancies occurring in 15 female patients (27 pregnancies) and partners of 8 male patients (15 pregnancies) with -thalassemia major who were successfully treated with allogeneic hematopoietic cell transplantation (HCT). Most pregnancies (n=21) were achieved with spontaneous conception in female patients. There were two miscarriages. Five pregnancies were late preterm. Delivery was vaginal in 4 cases and by caesarean section in 18. Overall, 22 term pregnancies resulted in successful deliveries of 23 neonates. Two of 23 neonates were symmetrical small for gestational age / intrauterine growth restriction. All 15 pregnancies that occurred in partners of men who received an allogeneic HCT were achieved with spontaneous conception. No miscarriage was observed. Overall, 14 term pregnancies resulted in successful deliveries of 14 live-born singletons. Delivery was vaginal in nine cases and by caesarean section in five. All infants were full-term. Many patients with -thalassemia major who received an allogeneic HCT retained or recovered their fertility after transplant. In these patients, pregnancy has been a practical and safe possibility and usually had a favorable outcome as in the normal population.Bone Marrow Transplantation advance online publication, 7 November 2016; doi:10.1038/bmt.2016.287.

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