Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study.

The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations. Other less common presentations included myelodysplastic syndromes (MDS) or MDS/MPN (one each). Four patients presented with B-lymphoblastic leukemia (B-ALL), and of them, two patients with t(8;9)(p22;p24.1) were proven to be B-lymphoblastic crisis of MPN; and the other two cases with t(9p24;v) both were de novo B-ALL, BCR-ABL1-like (Ph-like). We show that the hematopoietic neoplasms with 9p24/JAK2 rearrangement are extremely rare, and most of them are associated with t(8;9)(p22;p24)/PCM1-JAK2, a recent provisional World Health Organization entity under "myeloid/lymphoid neoplasm with a specific gene rearrangement". Cases of t(8;9)(p22;p24)/PCM1-JAK2, though heterogeneous, do exhibit some common clinicopathological characteristic features. Cases with t(9p24;v)/JAK2 are extremely rare; while such cases with a MPN presentation may resemble t(8;9)(p22;p24.1)/PCM1-JAK2, B-ALL cases presenting de novo B-ALL might belong to Ph-like B-ALL.

A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome.

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+ favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+ was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+ function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+ AML should be validated prospectively.

A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

This corrects the article DOI: 10.1038/leu.2016.303.

Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines.

While the role of nuclear transcription factor activator protein-1 (AP-1) in cell proliferation, and of nuclear factor-kappaB (NF-kappaB) in the suppression of apoptosis are known, their role in survival of prostate cancer cells is not well understood. We investigated the role of NF-kappaB and AP-1 in the survival of human androgen-independent (DU145) and -dependent (LNCaP) prostate cancer cell lines. Our results show that the faster rate of proliferation of DU145 cells when compared to LNCaP cells correlated with the constitutive expression of activated NF-kappaB and AP-1 in DU-145 cells. The lack of constitutive expression of NF-kappaB and AP-1 in LNCaP cells also correlated with their sensitivity to the antiproliferative effects of tumor necrosis factor (TNF). TNF induced NF-kappaB activation but not AP-1 activation in LNCaP cells. In DU145 cells both c-Fos and c-Jun were expressed and treatment with TNF activated c-Jun NH2-terminal kinase (JNK), needed for AP-1 activation. In LNCaP cells, however, only low levels of c-Jun was expressed and treatment with TNF minimally activated JNK. Treatment of cells with curcumin, a chemopreventive agent, suppressed both constitutive (DU145) and inducible (LNCaP) NF-kappaB activation, and potentiated TNF-induced apoptosis. Curcumin alone induced apoptosis in both cell types, which correlated with the downregulation of the expression of Bcl-2 and Bcl-xL and the activation of procaspase-3 and procaspase-8. Overall, our results suggest that NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin abrogates their survival mechanisms.

BCR rearrangement-negative chronic myelogenous leukemia revisited.

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement-negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients' molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation-negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement-negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement-negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement-negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

Effect of interferon-alpha therapy on bone marrow fibrosis in chronic myelogenous leukemia.

The aim of this study was to investigate the influence of interferon-alpha (IFN-alpha) on bone marrow fibrosis associated with chronic myelogenous leukemia (CML). Eighty-two bone marrow biopsies from 41 patients in chronic phase CML were stained with Snook's reticulin stain for argyrophilic fibers. Grading of reticulin fibrosis (scale of 1 to 4) was according to the quantity and pattern of distribution of reticulin. The interval between biopsies was a median of 25 months (range 12 to 40 months). Patients had been treated with IFN-alpha for at least 12 months, were still on IFN-alpha therapy during the study, and had achieved at least a complete hematological response. Before the start of IFN-alpha therapy, reticulin fibrosis was grade 1-2 in 23 patients (56%) and grade 3-4 in 18 (44%). During IFN-alpha therapy, reticulin fibrosis in bone marrow did not worsen or was reduced in 33 patients (80%) and increased by one grade in eight patients (20%). Only five patients (12%) with limited fibrosis (grade 1-2) before start of IFN-alpha therapy showed an increase towards significant fibrosis (grade 3-4), while eight of the 18 patients (44%) with grade 3-4 fibrosis achieved a decrease of fiber content in bone marrow. In summary, IFN-alpha was not associated with an enhancing effect on myelofibrosis in patients with CML and may have prevented increasing fibrosis in patients who respond to therapy.

Mature B-cell leukemias with more than 55% prolymphocytes. A heterogeneous group that includes an unusual variant of mantle cell lymphoma.

We studied 20 cases of mature B-cell leukemia with more than 55% prolymphocytes in peripheral blood or bone marrow, fulfilling the French-American-British criteria for B-cell prolymphocytic leukemia (PLL). Cases segregated into 3 groups: de novo PLL, 6; PLL occurring in patients with a previous well-established diagnosis of chronic lymphocytic leukemia (PLL-HxCLL), 10; and t(11;14)(q13;q32)-positive neoplasms, 4. All cases expressed monotypic immunoglobulin light chain, and most were positive for CD5. All t(11;14)-positive neoplasms were CD23- and uniquely positive for cyclin D1. Cytogenetic abnormalities were present in 19; in all 19, the karyotype was complex, indicating clonal evolution and genomic instability. The most frequent cytogenetic abnormality in de novo PLL involved chromosome 7 in 4 cases. Trisomy 12 or add(12p) was present in 4 cases of PLL-HxCLL. We conclude that mature B-cell leukemias with more than 55% prolymphocytes are a heterogeneous group that includes t(11;14)-positive neoplasms, which we suggest are best classified as mantle cell lymphoma. We also suggest that prolymphocytic morphologic features are a common end-stage of transformation for several B-cell neoplasms.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia associated with Hodgkin disease. A report of two cases.

Although the clinical course of lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is usually indolent, high-grade non-Hodgkin lymphoma may develop in a small subset of patients. We have not found any patients with LPL/WM associated with Hodgkin disease (HD) described in the literature, prompting us to report 2 cases. In case 1, the patient had LPL/WM involving bone marrow diagnosed 1 week before left supraclavicular lymph node biopsy revealed LPL/WM and classical HD. In case 2, the patient had a 15-year history of LPL/WM before classical HD developed involving bone marrow, liver, and lymph node. Both cases were positive for IgM, monotypic immunoglobulin light chain, and B-cell antigens and were CD3-. The neoplastic Hodgkin cells were CD15+, CD20+ (case 1), CD30+, CD3-, and CD45- and were negative for Epstein-Barr virus RNA. Both patients were treated with chemotherapy for HD. In case 1, clinical response was excellent with no histologic evidence of HD in subsequent biopsy specimens. In case 2, HD was progressive at last follow-up, despite therapy. Patients with LPL/WM, similar to patients with other types of low-grade B-cell lymphoma, can develop HD that may respond to chemotherapy.

Hepatosplenic gamma/delta T-cell lymphoma in bone marrow. A sinusoidal neoplasm with blastic cytologic features.

We report 8 cases of hepatosplenic T-cell lymphoma (HSTCL) involving bone marrow and correlate histologic findings with disease progression. Immunophenotypic analysis demonstrated mature, aberrant gamma/delta T-cell immunophenotypes. Isochromosome 7q was identified in 4 cases; 1 case showed the t(7;14)(q34;q13). Seven of 7 cases tested had monoclonal TCR gamma gene rearrangements. The initial diagnostic bone marrow biopsy specimens were hypercellular with a frequently subtle, predominantly sinusoidal infiltrate of atypical small to medium-sized lymphoid cells. In all cases, aspirate smears at diagnosis and in subsequent specimens contained malignant cells that resembled blasts, some with fine cytoplasmic granules. With progression, the pattern of HSTCL in bone marrow biopsy specimens became increasingly interstitial, and the neoplastic cells became larger. In aspirate smears, the proportion of blasts increased. Seven patients died; 1 was lost to follow-up. Autopsy performed on 1 patient demonstrated malignant cells within vascular channels in all organs sampled, with relatively little tumor formation, resembling intravascular lymphoma at these sites. HSTCL often can be recognized in bone marrow by its unique combination of a sinusoidal pattern in core biopsy specimens and blastic cytology in aspirate smears.

Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course.

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

Pathologic diagnosis of acute lymphocytic leukemia.

With present knowledge, the optimal management of individual patients with acute leukemia requires that every case be studied by morphology, cytochemistry, cytogenetic, immunologic and molecular techniques. An algorithm for diagnostic evaluation and classification of ALL is provided in Fig. 11. Other techniques, such as DNA or cDNA [figure: see text] microarray, are at present important research tools but have not yet had a major effect on patient care. More detailed studies of individual patients need to be conducted at specialized cancer centers, where preservation of cells, DNA, RNA, or protein is possible. Such investigations will yield important information on the clinical importance of the expression of various markers, the prevalence and relevance of bilineage and biphenotypic leukemias, and above all will reveal the mechanisms of leukemogenesis and of disease evolution. Such insights will further aid clinicians in treating ALL and in preventing refractory disease.

Multiple patterns of MDM-2 deregulation in human leukemias: implications in leukemogenesis and prognosis.

The human analogue of the mouse double minute-2 (MDM-2) protein binds to p53 protein and abrogates its tumor-suppressing activity. MDM-2 overexpression may represent an alternative mechanism to p53 mutation for escaping the p53-mediated growth control. Interestingly, multiple MDM-2 protein isoforms have been described and the possibility of functional differences between various isoforms has been raised. Previously, we demonstrated significant MDM-2 mRNA overexpression in human leukemias and suggested that MDM-2 overexpression may be a marker of aggressiveness of the disease. Polyclonal antibodies (Ab) have been generated to detect various isoforms of the MDM-2 protein. Using these Abs, we confirmed MDM-2 protein overexpression in leukemias. Furthermore, we observed heterogeneity in the isoforms expressed in various types of leukemias. In addition, we demonstrated that analysis by flow cytometry could be used as a diagnostic tool for detecting altered MDM-2 protein expression in leukemias. Here we review and expand our initial observations and confirm MDM-2 mRNA and protein overexpression by reverse transcription-polymerase chain reaction (RT-PCR), flow cytometry, and western blot analyses. Understanding the possible role of MDM-2 oncogene expression in leukemias may establish the scientific basis for new therapeutic approaches.

Terminal deoxynucleotidyl transferase expression in acute myelogenous leukemia and myelodysplasia as determined by flow cytometry.

The significance of terminal deoxynucleotidyl transferase (TdT) expression in acute myelogenous leukemia (AML) remains controversial. Therefore, we studied TdT expression by flow cytometry in 120 previously untreated patients with AML or myelodysplastic syndrome (MDS) to determine the distribution of TdT-positive blasts and the intensity of TdT expression and to seek clinically significant associations. TdT expression measured by flow cytometry (flow TdT%) was heterogeneous, ranging from 0.1% to 87% (median, 8.5%), and 74 patients (62%) had at least 5% TdT-positive blasts. TdT positivity was associated with the M0 or M1 subtype and with expression of CD34 and CD7. No significant correlation was found between TdT expression and type of cytogenetic abnormality or rearrangement of immunoglobulin or T-cell receptor genes. Remission lasted longer in patients with a flow TdT% < 5 than in patients with a flow TdT% > 5 (median, 95 weeks vs 55 weeks, p = 0.02); however, complete remission rates did not differ when patients were classified by initial flow TdT%. Survival was slightly better for patients with flow TdT% less than 5%. Among patients with a flow TdT% > 5%, those with a higher TdT intensity survived longer than those with a lower intensity. These data suggest that quantitative TdT measurement may contribute to prognostic estimate in AML patients.

Primary myeloid leukemia presenting concomitantly with primary multiple myeloma: two cases and an update of the literature.

We report one case of primary acute myelogenous leukemia (AML) and one case of refractory anemia with excess blasts in transformation (RAEB-T) each presenting concomitantly with multiple myeloma, an unusual finding. The twin diagnoses in each patient were confirmed by cytochemical and immunohistochemical studies, and in one of our cases, by ultrastructural, flow cytometric, and molecular studies. The last three methods have not been previously used to document this phenomenon.

Applicability of direct in situ reverse transcription-polymerase chain reaction on bone marrow smears.

In situ reverse transcription (RT)-polymerase chain reaction (PCR) is a promising laboratory tool for biomedical investigation at the molecular level in tissues. Direct in-cell amplification of the breakpoint cluster region (BCR)-Abelson (ABL) fusion transcript of chronic myeloid leukemia (CML) has recently been accomplished in Italy using bone marrow mononuclear cell suspensions. The goals of this study are to determine if in situ RT-PCR amplification is possible on bone marrow spirate smears and to demonstrate any unique factors in this procedure. A commercially available method was used because of the existence of published protocols for adaptation. Bone marrow (BM) aspirate smears (n = 17) from patients with CML in blast crisis (positive case material) or other hematological malignancies (negative case material) were evaluated. Satisfactory amplification of the BCR-ABL fusion transcript occurred, and distinct blue cytoplasmic granules that varied in intensity were found in most CML blasts. The negative case materials lacked the specifically amplified granular signals. Overall signal strength and backgrounds were readily affected by the quality of the specimen as well as by changes in assay parameters. In conclusion, the direct in situ RT-PCR technique is applicable for bone marrow aspirate smear evaluation. However, it remains an investigative tool until optimization for sensitivity, specificity, and accuracy can be achieved.

Acute myelomonocytic leukemia with histologic features resembling sarcomatoid carcinoma in bone marrow.

We report a case of primary acute myelomonocytic leukemia involving the bone marrow that resembled sarcomatoid carcinoma. The neoplastic cells in bone marrow biopsy specimens formed cohesive-appearing clusters and cords separated by an immature fibroblastic proliferation and myxoid stroma. Blasts in the bone marrow aspirate smears formed clusters and sheets, and a subset of blasts exhibited erythrophagocytosis. Dysgranulopoiesis was also present. Lineage was confirmed by immunohistochemical analysis of formalin-fixed, paraffin-embedded tissue. The tumor cells showed strong reactivity for lysozyme, myeloperoxidase, CD45, and CD68 and were negative for keratin, S100, CD20, and CD3. The serum lysozyme concentration (110 microgram/mL) was 13 times greater than the normal value (8 microgram/mL). Cytogenetic studies performed on bone marrow aspirate material revealed a complex karyotype, including trisomy 8 and abnormalities of chromosome 11q. We report this case of acute myelomonocytic leukemia because the neoplastic cells appeared cohesive and spindled, resembling sarcomatoid carcinoma, and therefore caused diagnostic difficulty. Other monocytic neoplasms with similar resemblance to carcinoma or sarcoma have been reported in the literature, suggesting that the tendency to appear cohesive may be an inherent characteristic of neoplastic cells with monocytic differentiation.

Natural killer-cell lymphoma involving the gynecologic tract.

Non-Hodgkin lymphomas (NHL) can involve the gynecologic tract, most often as a manifestation of systemic involvement, and most cases reported have been of B-cell lineage. We describe 2 women with natural killer (NK)-cell lymphoma involving the gynecologic tract that initially presented with vaginal bleeding. In case 1, the patient had a stage IE nasal-type NK-cell lymphoma involving the cervix. The tumor was composed of medium-sized, irregular lymphoid cells with angioinvasion and necrosis. In case 2, the patient had a stage IV blastoid NK-cell lymphoma/leukemia infiltrating all organs in a hysterectomy and bilateral salpingo-oophorectomy specimen. Subsequent biopsy specimens revealed that the bone marrow and lymph nodes were also involved. The neoplasm was composed of small to medium lymphoid cells with fine nuclear chromatin. Case 1 was assessed immunohistochemically and the neoplastic cells were positive for CD3, CD56, and TIA-1. Case 2 was analyzed using both immunohistochemical and flow cytometry methods. The neoplastic cells were positive for cytoplasmic CD3, CD4, CD7, CD43, CD45, and CD56 and were negative for surface CD3. Both cases were negative for Epstein-Barr virus (EBV) ribonucleic acid (RNA) and molecular studies showed no evidence of T-cell receptor gamma chain gene rearrangements. The immunophenotype and absence of T-cell receptor gene rearrangements support NK-cell origin. We report these cases to illustrate that NK-cell lymphomas can involve, and rarely arise in, the gynecologic tract.

Molecular study of hairy cell leukemia variant with biclonal paraproteinemia.

We report an unusual case of hairy cell leukemia variant with IgA and IgG-lambda biclonal gammopathy exhibiting light chain and a surface immunoglobulin class different from that of the paraproteins. In addition, we documented by gene rearrangement study that the hairy cell leukemia variant clone appears independent from the paraprotein-producing cells. The kappa light chain was expressed on the surface of hairy cell leukemia variant cells. Southern blot analysis revealed rearrangement of the kappa-light-chain gene and germline configuration of lambda-light-chain gene. We observed significant clinical improvement and reduction in the leukemic infiltrate in the patient after treatment with 2-chlorodeoxyadenosine (2-CdA). The intensity of the rearranged kappa-light-chain gene band decreased with therapy and increased at relapse without significant change of the paraproteins. Previously reported cases of hairy cell leukemia variant with paraproteins are reviewed, and our patient's contribution to the understanding of this association is stressed.