Kiyonori Takada

Successful treatment of transfusion‐associated graft‐versus‐host disease

Summary. We present an immunocompetent patient with transfusion‐associated graft‐versus‐host disease (GVHD), in which chimaerism of peripheral blood lymphocytes was demonstrated by analysis of a highly polymorphic genome. The patient was treated successfully with anti‐CD 3 monoclonal antibody, OKT3 and cyclosporin A. Although it is undoubtedly important to prevent transfusion‐associated GVHD by irradiation of cellular blood components, intensive therapy with OKT3 and cyclosporin A in the early phase of onset may be effective for treatment of this potentially fatal condition. The mechanism of the effectiveness of this treatment for transfusion‐associated GVHD is discussed.

Neoplastic involvement of granulocytic lineage, not granulocytic-monocytic, monocytic, or erythrocytic lineage, in a patient with chronic neutrophilic leukemia case report

Chronic neutrophilic leukemia (CNL) is a very rare myeloproliferative disorder. To determine the neoplastic origin of CNL, morphological and cytogenetical studies were made of colonies derived from hematopoietic progenitors of a patient with CNL. The patients hematopoietic progenitors spontaneously formed colonies consisting of mature granulocytes, and cytogenetical study of the colonies indicated chromosome abnormalities identical to those in the patients bone marrow cells. Analysis of colonies consisting of granulocytes and macrophages, macrophages, or erythrocytes disclosed a normal karyotype. These results demonstrated that the neoplastic process in this patient with CNL originated in hematopoietic progenitors capable of differentiating only into granulocytes, and not granulocytes and monocytes, monocytes, or erythrocytes. Am. J. Hematol. 57:221–224, 1998.

Phenotypic and genotypic analysis of chronic myelogenous leukaemia with T lymphoblastic and megakaryoblastic mixed crisis

A case of blast crisis in chronic myelogeneous leukaemia (CML) in which two distinct cell lineages were involved is presented. The phenotype of blasts in lymph nodes was T11 (CD2)+, Ia+, TdT+, suggesting T cell lineage. On the other hand, blasts in bone marrow and peripheral blood expressed platelet glycoprotein IIb/IIIa complex on their surface, suggesting megakaryocyte lineage. Cytogenetic analysis of lymph node and bone marrow cells revealed the abnormalities. inv(7) (p15q34) and t(1;3) (q23;q21), respectively, as well as the presence of the Ph1 chromosome in both cell types. Rearrangement of the T cell receptor β‐chain gene was detected in lymph node blasts, although blast cells in peripheral blood showed a germ line configuration. The involvement of T cell and megakaryocyte lineages in the blast crisis phase of CML was confirmed in our phenotypic and genotypic analysis, and the pathogenic association between blast crisis lineages and the additional chromosome abnormalities present is discussed.

Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus Darunavir/r in patients with suppressed viral load did not result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial.

Background Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load. Methods This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation. Results 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD). Conclusions Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load. Trial Registration ClinicalTrials.gov NCT01294761 http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J)

Dramatic efficacy of fludarabine in the treatment of an aggressive case of splenic lymphoma with villous lymphocytes

Abstract: Splenic lymphoma with villous lymphocytes (SLVL) is an indolent lymphoproliferative disorder of mature B lymphocytes. Splenectomy is primarily recommended for treating this disease, and splenic irradiation or alkylating agents may be effective; however, frequent recurrence is observed after these therapies. We report here an unusual case of SLVL in which the degree of splenomegaly and the serum IgM level increased rapidly. Although the effects of splenic irradiation and combination chemotherapy were both unsatisfactory and transient, complete remission lasting for more than 15 months was achieved after two courses of treatment with low‐dose fludarabine (15 mg m−2 daily for 3 d). The present case indicates that treatment with fludarabine is effective for SLVL and recommended as the first‐line therapy for elderly patients and those with an aggressive form of the disease.

Non-Hodgkin's lymphoma developing in a pacemaker pocket

A 29-year-old man developed diffuse large B-cell lymphoma in a subpectoral pacemaker pocket that 6 years previously had been created in the chest for a titanium-covered pulse generator. The patient had an 8-cm—diameter dark red tumor with necrotic tissue on a keloidal surgical scar in the left side of the chest. Left axillary lymphadenopathy also was present. Laboratory studies showed an increased level of soluble interleukin 2 receptor and a normal level of lactose dehydrogenase. A biopsy specimen showed a diffuse large B-cell phenotype and monoclonal immunoglobulin H gene rearrangement. A gallium scintigraphy study showed abnormal accumulation in the left chest and left axilla. On the basis of these findings, we diagnosed diffuse large B-cell lymphoma, stage II. The patient received THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone) and radiotherapy, achieved complete remission, and was free of disease for 16 months after treatment. This case suggests that there was a relationship between the development of non-Hodgkin’s lymphoma and the presence of chronic inflammation in the pulse generator pocket.

Existence of Leukemic Clones Resistant to Both Imatinib Mesylate and Rituximab before Drug Therapies in a Patient with Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20- leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.

Acute Transformation of Chronic Large Granular Lymphocyte Leukemia into an Aggressive Form Associated with Preferential Organ Involvement

In most patients with large granular lymphocyte (LGL) leukemia, the disease appears to progress slowly if at all, and no therapy is generally required. We present a patient with CD3+ CD8+ CD16+ LGL leukemia, who showed a benign clinical course for more than 7 months without therapy, but subsequently developed aggressive disease. A feature of considerable interest was the transformation into an acute or aggressive form in this patient affected preferentially the liver and spleen, and was not associated with the hematologic features of the circulating leukemic cells, as assessed by morphologic, phenotypic and molecular analyses. The patient was treated with combination chemotherapy; this resulted in clinical remission with persistence of the abnormal clone in the peripheral blood. The mechanism responsible for the preferential organ involvement and the process of progression from the chronic to the acute form in this case are discussed from the viewpoint of a lymphoproliferative disorder.

Proliferation of double‐negative (CD4−CD8−) T cells bearing T‐cell receptor‐αβ in a haemophiliac with human immunodeficiency virus type 1 infection and factor VIII inhibitor: functional properties of double‐negative T‐cell receptor‐αβ+ T cells

We present a patient with haemophilia A showing human immunodeficiency virus type 1 (HIV‐1) infection and factor VIII inhibitor in whom a novel T‐cell subpopulation, double‐negative (CD4−CD8−) T cells bearing T‐cell receptor (TCR)αβ, proliferated polyclonally in the peripheral blood. An interleukin‐2‐dependent T‐cell line with a CD4−CD8−TCR‐αβ+ phenotype was established from the peripheral blood lymphocytes of the patient, and its biological functions were studied. It was found that the CD4−CD8−TCR‐αβ+ T cells possessed both HLA‐unrestricted cytotoxicity and helper function for immunoglobulin production by B cells. In addition, these T cells were found to produce interferon‐γ and interleukin‐2 following activation via CD3‐TCR complexes. These data demonstrating the multifunction of these newly defined CD4−CD8−TCR‐αβ+ T cells thus suggest that these cells play an important role in protection against HIV infection. The mechanism of production of factor VIII inhibitor in the present case is also discussed focusing on the CD4−CD8−TCR‐αβ+ T cells.

Monoclonal proliferation of double‐negative (CD4−CD8−) T‐cells bearing T‐Cell receptor‐αβ followed by subsequent development of Hodgkin's disease

Expression of CD4 or CD8 on the cell surface is an important guide for discriminating the immunologic functions of T‐cells. However, a minor T‐cell subset lacking both CD4 and CD8 molecules but bearing the usual form of T‐cell receptor (TCR)‐αβ (CD4−CD8−TCR‐αβ+ T‐cells) has recently been found not only in mice but also in humans, and the clinical relevance of this newly defined subpopulation to human diseases is now of considerable interest. The authors present a patient in whom CD4−CD8−TCR‐αβ+ T‐cells showed monoclonal proliferation in the peripheral blood for more than 3 years, then disappeared spontaneously, followed by subsequent development of Hodgkins disease. The pathologic roles of double‐negative T‐cell proliferation in this case are discussed from the viewpoint of premalignancy in lymphoproliferative diseases. Cancer 1994; 73:2818–23.