To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid ...(dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen.
Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment.
A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%).
SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.
1 Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama;
2 Department of Pathology, Tokai University School of Medicine, Kanagawa;
3 ...Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo;
4 Department of Pathology, St. Marianna University School of Medicine, Kawasaki;
5 Department of Chemotherapy, Kanagawa Cancer Center, Yokohama;
6 Division of Hemato-oncology, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama;
7 Department of Hematology, Tokai University School of Medicine, Kanagawa;
8 Department of Hematology, Yokohama City University Medical Center, Yokohama;
9 Cancer Center, Ehime University Graduate School of Medicine, Ehime;
10 Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa;
11 Department of Internal Medicine, Okayama Red Cross General Hospital, Okayama;
12 Division of Hematology, Tenri Hospital, Nara and
13 Division of Hematology and Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
Correspondence: Naoto Tomita, M.D., Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan E-mail: cavalier{at}ch-yamate.dlenet.com
Background: Lymphoid neoplasm with 18q21.3/ BCL2 and 8q24/ MYC translocation to immunoglobulin ( IG ) genes as dual-hit lymphoma/leukemia is very rare and known to have a poor clinical outcome.
Design and Methods: To clarify the clinicopathological characteristics of this malignancy, we analyzed 27 cases of cytogenetically proven dual-hit lymphoma/leukemia.
Results: Dual-hit lymphoma/leukemia was diagnosed at presentation in 22 cases and at relapse or disease progression in 5 cases. At the time of diagnosis of dual-hit lymphoma/leukemia, extranodal involvement was found in 25 cases (93%) and central nervous system involvement occurred in 15 cases (56%). The median survival and 1-year survival rate of the 27 cases were only 6 months and 22%, respectively, after diagnosis of the dual-hit lymphoma/leukemia. Seven cases of triple-hit lymphoma/leukemia (dual-hit lymphoma/leukemia with 3q27/ BCL6 translocation) were included; the median survival of these patients was only 4 months from the diagnosis of the dual-hit lymphoma/leukemia. The duration of survival of the patients with a triple-hit malignancy was shorter than that of the other 20 cases of dual-hit lymphoma/leukemia ( p =0.02). The translocation partner of MYC subdivided the dual-hit cases into two groups; 14 cases of IGH and 13 cases of IGK/L . The MIB-1 index was investigated in 14 cases with aggressive B-cell lymphoma, and was higher in the group with MYC-IGH translocation (n=7) than in the MYC-IGK/L group (n=7) ( p =0.02). Overall survival was not different between the MYC-IGH translocation group (n=14) and the MYC-IGK or MYC-IGL translocation group (n=13).
Conclusions: Dual-hit lymphoma/leukemia is a rare but distinct mature B-cell neoplasm with an extremely poor prognosis characterized by frequent extranodal involvement and central nervous system progression with either of the translocation partners of MYC .
Key words: BCL2 , MYC , dual-hit lymphoma/leukemia.
Related Article
Novel lymphoid neoplasms – the borderland between diffuse large B-cell lymphoma and Burkitts lymphoma
Daphne de Jong
Haematologica 2009 94: 894-896.
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Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse ...large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy.
Patients and methods: We studied 375 consecutive patients who were newly diagnosed with DLBCL between 1996 and 2006. Patients with primary CNS involvement and patients who received CNS prophylaxis were excluded. All the patients received CHOP (n = 172) or R‐CHOP (n = 203) chemotherapy. The following variables were assessed for their potential to predict CNS involvement: gender, age, serum lactate dehydrogenase (LDH) level, performance status, clinical stage, number of extranodal involvements, International Prognostic Index (IPI), bone marrow involvement, presence of a bulky mass, presence of B symptom, and treatment.
Results: CNS involvement was observed in 13 cases (3.5%). In univariate analysis, LDH more than normal range, LDH more than twice as normal range, high IPI, bone marrow involvement, and systemic relapse were the predictors for CNS involvement. In multivariate analysis, no risk factors were detected for CNS involvement. The use of rituximab did not have an impact on CNS involvement.
Conclusions: The incidence of CNS involvement dose not decrease in rituximab‐era.
For patients with relapsed acute promyelocytic leukemia (APL), all‐trans retinoic acid‐based salvage regimens can achieve second complete remission (CR2), but the optimal post‐remission strategy for ...APL patients after CR2 remains unclear. Hematopoietic stem cell transplantation (HSCT) during CR2 might be effective, but data on the role of HSCT for APL patients after CR2 are limited in Japan. We retrospectively analyzed outcomes for 57 relapsed APL patients who achieved CR2 in the JALSG APL97 study. Of those, six received autologous (auto)‐HSCT, 21 received allogeneic (allo)‐HSCT, and 30 received various regimens other than HSCT. The 5‐year event‐free survival (EFS) rate, overall survival (OS) rate and cumulative incidence of relapse (CIR) were 50.7%, 77.4% and 51.0% in the non‐HSCT group, 41.7%, 83.3% and 58.3% in the auto‐HSCT group and 71.1%, 76.2% and 9.8% in the allo‐HSCT group, respectively. Both the EFS rate and CIR were significantly better in the allo‐HSCT group than in other groups. Allo‐HSCT appears effective in APL patients in CR2, with a low relapse rate beyond a relatively early transplantation‐related mortality (19%). Among older patients (age ≥40 years), the 5‐year OS was significantly better in the non‐HSCT group than in the HSCT group (78.0% vs 40.5%; P = 0.04). Further prospective studies with larger patient numbers are required to confirm the impact of HSCT alone and in combination with arsenic trioxide on outcomes for patients with APL in CR2.
We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for ...acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0–95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥1,000 ng/ml,
n
= 57) than in the low (<1,000 ng/ml,
n
= 57) ferritin group (42.1 versus 21.1%, respectively,
P
= 0.017). Peripheral blood stem cell transplantation (PBSCT) (
n
= 23) showed a greater protective effect against BSI compared with bone marrow (
n
= 71) and cord blood (
n
= 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180–6.859,
P
= 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025–0.717,
P
= 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.
Purpose To elucidate the management and outcomes of patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKL), who were diagnosed between 2000 and 2013 in Japan. Patients and Methods ...Data from 358 patients with ENKL diagnosed between 2000 and 2013 from 31 institutes were retrospectively analyzed. Results Patients' median age was 58 years, and 257 (72%) had localized disease. The most common first-line treatment was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%) for localized ENKL and L-asparaginase-containing chemotherapy (30%) for advanced ENKL. With a median follow-up of 5.8 years, overall survival (OS) rates at 5 years for localized and advanced ENKL were 68% and 24%, respectively. The prognostic index of natural killer lymphoma was validated in our study, although only 4% of patients with localized ENKL were classified as high risk. With a median follow-up of 5.6 years, OS and progression-free survival at 5 years in the 150 patients who received RT-DeVIC in clinical practice were 72% (95% CI, 63% to 78%) and 61% (95% CI, 52% to 69%), respectively. Toxicities of RT-DeVIC were comparable to those in a previous trial. Multivariate analysis in patients with localized ENKL who received RT-DeVIC identified elevated soluble interleukin-2 receptor as an independent predictive factor for worse OS and progression-free survival (adjusted hazard ratios, 2.28 and 2.46; 95% CI, 1.24 to 4.23 and 1.42 to 4.28; P = .008 and .0014, respectively). Conclusion Favorable OS in response to new treatments was demonstrated in a large number of patients. Improved treatment approaches are needed for localized ENKL exhibiting elevated pretreatment soluble interleukin-2 receptor.
We investigated a fixed scheme of combination chemotherapy protocol including CHOP, granulocyte colony stimulating factor (G-CSF) and rituximab (CHOP-GR) for patients with diffuse large B cell ...lymphoma (DLBCL) in a phase II clinical trial. Forty-four patients were registered: 21 patients <61 years of age in the low or low-intermediate International Prognostic Index (IPI) risk group and 23 patients between 61 and 70 years of age in any IPI risk group. The patients underwent two courses of CHOP chemotherapy followed by four courses of CHOP-GR, including subcutaneous G-CSF on days 11–14 and rituximab on day 15. An additional two courses of weekly rituximab were administered. Of the assessable 43 patients, complete remission occurred in 39 (91 %), partial remission in one (2 %), and progressive disease in three (7 %). In the median 53-month observation period in alive patients, the 5-year overall survival rate of the 43 patients was 77 % and the 5-year progression-free survival rate was 69 % with a subsequent plateau. There were nine deaths in the 43 patients, all of which were attributable to lymphoma progression. The most frequent adverse events were leukocytopenia (98 %), neutropenia (94 %), lymphocytopenia (91 %), and alopecia (83 %). CHOP-GR is a safe and effective therapy for patients with untreated DLBCL.
Abstract 2920
Poster Board II-896
Epstein-Barr virus (EBV) is currently recognized as a pathogen of several known human diseases ranging from transient infection, chronic lymphoproliferative disorder ...(LPD) to EBV-positive malignant lymphomas. Chronic active EBV infection (CAEBV) is typically an indolent but long-lasting EBV-LPD of childhood. Another well documented EBV-associated LPD is the post-transplant EBV-LPD, which also occurs in adults. Fulminant proliferation of EBV after primary infection or in the setting of CAEBV is an aggressive type of disease, which has recently been included in the 4th version of WHO classification as “systemic EBV-positive T-cell LPD of childhood”. Here, we present a previously unrecognized type of EBV-associated LPD mainly developed in adults who experienced progressive clinical course.
A total of 13 adult patients with progressive EBV-LPD was identified from patient files of collaborative institutions. The patient clinical records and data were investigated retrospectively.
There were six males and seven females with an age ranging from 16 to 85 years (median: 27 years). All patients were previously healthy without history of opportunistic infections or administration of immunosuppressants. Patients presented with persistent fever, hepatosplenomegaly and cytopenia, and all showed increasing number of EBV-DNA copies in peripheral blood. Proliferation of T- or NK-cells was recognized. Four patients showed elevated VCA-IgM antibody, and fell in the category of fulminant EBV-positive T-cell LPD after primary EBV infection. However, the other nine showed EBV-antibodies of previous infection. The bone marrow, liver, and lymph nodes were common sites of involvement. Morphological atypia of lymphocytes were faint in peripheral blood or biopsied specimens. Therefore, pathological diagnosis of malignant condition was difficult at the initial presentation. Because of the deteriorating clinical conditions, chemotherapy was administered to 12 patients, but the disease was resistant in 10 patients. Four patients underwent allogeneic hematopoietic stem cell transplantation. In total, 3 patients are alive and 10 patients were dead. The causes of death were primary disease in 5 patients, bleeding in 2, infection in 2, but unknown in one. All but one patient without allogeneic transplantation died within a year. The median survival time was eight months.
In contrast to CAEBV in childhood, these 13 adult patients pursued obviously different, more aggressive clinical courses. However, early diagnosis had been difficult because of the little morphological abnormalities and disease recognition. Prompt administration of cytotoxic chemotherapy and/or stem cell transplantation is possibly needed to conquer this aggressive disease. Therefore, for this purpose, we here propose a novel nomenclature of progressive adult-onset EBV-LPD (PAEBV). PAEBV is (1) the disease with increasing number of EBV-DNA in T or NK cells, (2) the malignant disease without or mild atypia in its early stage, and (3) associated with a poor prognosis. For adolescence or young adults, both classical CAEBV and PAEBV can be recognized. Further investigations for differential diagnosis are required, as well as those for appropriate therapeutic approaches against this rare and intractable disease.
No relevant conflicts of interest to declare.
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