Remission Of Hairy Cell Leukemia Research Articles

Initial characterization of an immunotoxin constructed from domains II and III of cholera exotoxin

Immunotoxins are antibody-toxin fusion proteins under development as cancer therapeutics. In early clinical trials, immunotoxins constructed with domains II and III of Pseudomonas exotoxin (termed PE38), have produced a high rate of complete remissions in Hairy Cell Leukemia and objective responses in other malignancies. Cholera exotoxin (also known as cholix toxin) has a very similar three-dimensional structure to Pseudomonas exotoxin (PE) and when domains II and III of each are compared at the primary sequence level, they are 36% identical and 50% similar. Here we report on the construction and activity of an immunotoxin made with domains II and III of cholera exotoxin (here termed CET40). In cell viability assays, the CET40 immunotoxin was equipotent to tenfold less active compared to a PE-based immunotoxin made with the same single-chain Fv. A major limitation of toxin-based immunotoxins is the development of neutralizing antibodies to the toxin portion of the immunotoxin. Because of structure and sequence similarities, we evaluated a CET40 immunotoxin for the presence of PE-related epitopes. In western blots, three-of-three anti-PE antibody preparations failed to react with the CET40 immunotoxin. More importantly, in neutralization studies neither these antibodies nor those from patients with neutralizing titers to PE38, neutralized the CET40-immunotoxin. We propose that the use of modular components such as antibody Fvs and toxin domains will allow a greater flexibility in how these agents are designed and deployed including the sequential administration of a second immunotoxin after patients have developed neutralizing antibodies to the first.

Concomitant hairy cell and acute myeloid leukemia

Secondary malignancies in patients with hairy cell leukemia (HCL) are well described and treatment of HCL is discussed as their cause. We describe a 58-yr-old patient who presented with both acute myeloid leukemia (AML) and HCL at the same time. Treatment with cladribine, daunorubicin and cytosine arabinoside, followed by autologous stem cell transplantation, induced complete remission of AML and hematologic remission of HCL for 22 months, when he relapsed with AML. This concomitant occurrence of AML and HCL is suggestive of a genetic predisposition rather then coincidence or relation to purine analoga.

Long remissions in hairy cell leukemia with purine analogs

Both pentostatin and cladribine have efficacy in hairy cell leukemia (HCL), but it is not known which agent achieves better results. We reviewed a series of 219 patients with HCL, with median follow-up from diagnosis of 12.5 years (range 1.0 -34.6 yrs), treated with either pentostatin (n = 185) or cladribine (n = 34), to compare these agents and assess the potential for cure. Overall response to pentostatin was 96% with a complete response (CR) in 81% and a median disease-free survival (DFS) of 15 years. Response to first-line cladribine was 100% with a CR in 82% and DFS of 11+ years. The relapse rates at 5 years and 10 years were 24% and 42%, respectively, with pentostatin, and 33% and 48% with cladribine. Survival at 10 years was respectively 96% and 100%. CR rates decreased with each sequential relapse through 69% to 45% (P < or = 0.001). Patients achieving CR after first-line treatment had a significantly longer DFS (P = 0.00007) than those achieving a partial response; a similar result was seen after second-line therapy (P = 0.00001). DFS also declined with sequential treatment (P = 0.00005). We have shown equivalent efficacies for both agents in the treatment of HCL, with DFS showing no plateau. True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment.

Phase II study of cladribine (2CDA) followed by rituximab for eradication of minimal residual disease (MRD) in hairy cell leukemia (HCL)

6620 Background: HCL is an indolent lymphoproliferative malignancy characterized by infiltration of the bone marrow, liver, and spleen by neoplastic B-cells with cytoplasmic hair-like projections. Despite the success of the nucleoside analogs 2CDA and pentostatin in achieving long-term remissions in HCL, some patients (pts) continue to relapse and the relapse-free survival curve does not appear to achieve a plateau. Rituximab has been used effectively to treat pts with relapsed HCL. We investigated whether the prolonged administration of rituximab one month after therapy with 2CDA can effectively eradicate MRD in pts with newly diagnosed HCL or those who have relapsed after one prior therapy. Methods: 2CDA 5.6 mg/m2 is administered over 2 hours daily for 5 days. One month later, rituximab 375 mg/m2 is administered weekly for 8 weeks. MRD is assessed by flow cytometry as well as by IgH polymerase chain reaction (PCR) assay using framework-1, -2 and -3 primer sets. MRD is evaluated at one month following 2CDA and after completion of rituximab. Results: To date, ten pts have been enrolled onto the study. Eight pts had received no prior therapy, one pt had relapsed after prior 2CDA therapy 9 years ago and one pt had received chlorambucil only. Two pts had the variant form of HCL. Six pts have completed all therapy, 3 are receiving rituximab, and 1 pt has completed 2CDA only. So far, six (100%) of the evaluable pts have achieved a complete remission (CR) with no evidence of MRD by flow in 6 and by PCR in 3. PCR remained positive in 1 pt and was not evaluable in 2 pts. Eight of 9 pts with evaluable flow studies one month after completing 2CDA remained positive; 1 pt was negative after 2CDA only and 6 became negative after completing rituximab. Five of 6 pts with evaluable PCR studies one month after completing 2CDA remained positive; 1 pt was negative after 2CDA only and 3 became negative after rituximab. Conclusions: We conclude that assessment and eradication of MRD by flow and PCR in HCL is feasible. Longer follow-up is necessary to determine whether MRD status at completion of therapy can predict relapse. This may allow design of regimens that may further improve long-term disease-free survival in HCL. No significant financial relationships to disclose.

A Case of Complete Remission of Hairy Cell Leukemia by 2-Chlorodeoxyadenosine

Hairy cell leukemia (HCL) is an uncommon chronic B-cell lymphoproliferative disorder that is characterized by cytopenia, splenomegaly, and mononuclear cells displaying cytoplasmic projections. We experienced a case of hairy cell leukemia that developed in a 38-year-old man. He showed marked splenomegaly without palpable lymphoadenopathy. A complete blood cell count revealed leukopenia ( with 63% of lymphocyte) and the peripheral blood smear showed abnormal lymphoid cells with cytoplasmic projections. The bone marrow smear revealed abnormal lymphocytes and severe myelofibrosis. Tartrate-resistant acid phosphatase reactivity was strongly positive in the hairy cells. The immunophenotyping results of lymphoid cells were CD5(-), CD10(-), CD19(+), CD25(+), CD103(+), CD20(+), lambda(+). The patient was treated with 2-Chlorodeoxyadenosine at a daily dose of 0.1mg/Kg by a continuous intravenous infusion for 7 days. The patient achieved complete remission.

Minimal Residual Disease in Hairy-cell Leukemia after Treatment with 2-chlorodeoxyadenosine

ABSTRACT Some patients in apparent complete remission of hairy cell leukemia (HCL) after 2-chlorodeoxyadenosine (2-CdA) treatment may have minimal residual disease (MRD). This study examines detection of minimal residual disease by immunohistological staining using the monoclonal antibody (MoAb) B-ly 7 in 11 patients with complete remission of hairy cell leukemia (HCL) after 2-CdA therapy between 1990 and 1993. In all 11 cases, residual hairy cells could be detected by MoAb B-ly 7 (0.1 to 7.5 %, median 0.65 %). At a median follow-up period of 7 - 29 (median 19.3) months, 9 of these patients remained in complete remission, whereas 2 patients relapsed 22 and 27 months after 2-CdA therapy. To determine whether flow-cytometric analysis of hairy-cells in bone marrow aspirates and peripheral blood cells are comparable with results obtained by immunostaining with B-ly 7 in bone marrow biopsies, available data using CD-19/CD-11c double-staining were analyzed. In 5 of 10 cases no hairy-cells could be detected in bone marrow aspirates, and in 6 partly different cases no hairy-cells were detectable in peripheral blood using flow-cytometry, although immunostaining of bone marrow biopsies using B-ly 7 revealed hairy-cells (ranging from 0.1 to 7.5 %) in these cases. These results indicate that therapy with 2-CdA does not eradicate hairy cell leukemia despite complete remission according to conventional criteria. Minimal residual disease might be responsible for subsequent relapse. We conclude that routine immunohistological examination of bone marrow biopsies with B-ly 7 should be performed for assessment of MRD. Flow cytometric investigations of mononuclear cells of bone-marrow aspirate or peripheral blood seem valuable for regular long term monitoring of MRD, but does not substitute for immunostaining of bone marrow biopsies.

Complete hematologic remissions in chronic-phase, philadelphia-chromosome-positive, chronic myelogenous leukemia after 2-chlorodeoxyadenosine

2-Chlorodeoxyadenosine (Cladribine, Leustatin, Ortho Biotech, Raritan, NJ) (2-CdA) is a purine analog with activity in the treatment of lymphoid neoplasms. Interferon induces cytogenetic remissions in chronic myeloid leukemia (CML) and partial remissions in hairy cell leukemia, a disorder in which single courses of 2-CdA induce complete remissions. In vitro clonal growth of immature myeloid progenitors from normal marrow is markedly inhibited by 2-CdA. 2-CdA was administered to 12 patients with Philadelphia-chromosome-positive CML, 11 chronic phase, and 1 accelerated phase, at 0.1 mg/kg/day by continuous intravenous infusion for 7 days every 28-35 days, until maximum peripheral hematologic response. Of 12 patients, 10 (83%) achieved complete hematologic responses and 2 (17%) partial hematologic responses after a median of two courses of 2-CdA. The median first hematologic response duration was 3 months. Of the seven patients who relapsed and were retreated with a median of two further courses of 2-CdA, five obtained responses (four complete and one partial) and two did not respond. The median second hematologic response duration was 4 months. No patient had significant Philadelphia-chromosome suppression. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in four patients were the principal toxicities. 2-CdA is active in CML, inducing complete hematologic responses, but the absence of cytogenetic responses and severe immunosuppression may limit its clinical use.

Complete Remissions in Hairy Cell Leukemia with 2-Chlorodeoxyadenosine after Failure with 2-Deoxycoformycin

To determine whether clinical cross-resistance and intolerance exists between the nucleosides 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) in the treatment of patients with hairy cell leukemia despite similar structures and mechanisms of action. Phase II clinical study. Referral cancer center. Five patients with hairy cell leukemia who had been previously treated with DCF. Single course of 2-CdA at 0.1 mg/kg body weight per day for 7 days by continuous intravenous infusion. Of five patients, three were resistant to and two were intolerant of (having had life-threatening toxic reactions) DCF therapy. Four patients obtained a complete response with a median follow-up period of more than 11 months. The other patient in whom splenectomy, interferon, and DCF treatments were unsuccessful had a partial response lasting 2 months and subsequently died of Streptococcus pneumoniae bacteremia. Three of the four patients with complete responses remain in unmaintained remission, whereas the fourth has progressive splenic enlargement with stable hematologic parameters. The median leukocyte count increased from 2.0 x 10(9)/L to 3.8 x 10(9)/L, the median absolute neutrophil count increased from 0.56 x 10(9)/L to 2.73 x 10(9)/L, the median hemoglobin level increased from 112 g/L to 140 g/L, and the median platelet count increased from 55 x 10(9)/L to 123 x 10(9)/L. Two patients had culture-negative neutropenic fever associated with treatment. 2-Chlorodeoxyadenosine induced complete responses in patients with hairy cell leukemia resistant to DCF, suggesting a lack of cross-resistance. Also, 2-CdA is not prohibitively toxic in patients intolerant of DCF.

Pentostatin induces durable remissions in hairy cell leukemia.

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

Low Dose Interferon Alfa-2B for the Induction of Remission of Hairy Cell Leukemia: A Multi-institutional Study of 49 Patients.

This multicenter study reports on 49 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corporation, Kenilworth, N.J.), three times a week at a reduced dosage of 200,000 units/m(2), one-tenth the dose of the standard 2 million units/m(2). The response rate (normalized blood counts) was 22% (11 of 49); an additional 12 patients had a minor response for an overall response rate of 47% (23 of 49). When response was assessed by prior IFN therapy, no significant difference was noted. Five of 21 (24%) with no prior IFN and 6 of 28 (21%) with prior IFN therapy achieved at least a normalization of blood counts (p = 0.07). The response rate with low-dose interferon is inferior to that with standard dose interferon and should not be used for remission induction, but should be evaluated for its role in long-term maintenance of response.

Lasting Remissions in Hairy-Cell Leukemia Induced by a Single Infusion of 2-Chlorodeoxyadenosine

2-Chlorodeoxyadenosine is a simple purine nucleoside that has previously been shown to be effective in the treatment of low-grade malignant disorders of lymphoid tissue, including chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Because of these encouraging results, we treated 12 patients with another low-grade B-cell neoplasm, hairy-cell leukemia. The patients received 2-chlorodeoxyadenosine (0.1 mg per kilogram of body weight per day) by continuous infusion for seven days. All the patients responded to treatment. Eleven had complete remissions characterized by the normalization of peripheral blood and bone marrow and disappearance of tumor masses. The longest remission has been 3.8 years. None of the patients have relapsed, and the median duration of remission has been 15.5 months. No serious toxic reactions occurred as a result of 2-chlorodeoxyadenosine therapy. These results suggest that 2-chlorodeoxyadenosine may be the most effective therapy available for hairy-cell leukemia. The administration of 2-chlorodeoxyadenosine resulted in a higher rate of complete remission than is observed with interferon alfa, and it required no maintenance therapy. Its toxicity may be lower than that of deoxycoformycin, and the responses were achieved with single courses of treatment.

Action of interferon-alpha on hairy cell leukemia: Expression of specific receptors and (2′–5′)oligo (a) synthetase in tumor cells from sensitive and resistant patients

IFN- α induces tumor regression with a high percentage of complete remissions in hairy cell leukemia. We have recently reported that hairy cells express specific IFN- α receptors which are down-regulated upon therapy. We show here that the activity of 2–5 A synthetase, an IFN-induced enzyme, is 2 to 7-fold stimulated in hairy cells from responsive patients within 12–24 h after the first IFN dose. This in-vivo enzyme induction paralleled the kinetics of receptor down-regulation. In one patient who was unresponsive to IFN- α treatment neither expression of IFN- α receptor nor change in 2–5 A synthetase could be detected, whereas in a second unresponsive patient, both receptors and 2–5 A synthetase were expressed and modulated as in sensitive patients. In-vitro treatment of hairy cells with recombinant interferons showed that IFN- β1 was able to induce this enzyme to the same extent than IFN- α2, whereas IFN- γ was inactive despite the presence of specific IFN- γ receptors. Our results indicate that IFN- α can exert its therapeutic effects by acting directly on the hairy cells through interaction with surface membrane receptors. Induction of 2–5 A synthetase can be one of the steps involved in this action. However, both mechanisms, as well as receptor down-regulation are not sufficient to explain the responsiveness of hairy cell leukemia to IFN- α.

Remissions in Hairy-Cell Leukemia with Pentostatin (2′-Deoxycoformycin)

The Eastern Cooperative Oncology Group conducted a study of pentostatin (2'-deoxycoformycin) in 37 patients with hairy-cell leukemia. Among the 27 patients who met all the study's entry criteria, the response rate was 96 percent, with 16 patients (59 percent) entering complete remission and 10 patients (37 percent) partial remission. In one patient no response was observed. These results were not significantly changed by the inclusion of nine additional patients who were found retrospectively not to have fulfilled the entry criteria. When complete remission was attained, maintenance therapy was not given. Despite this, no patient has had a relapse, and the duration of complete remission ranges from 1 to 375 days. Pentostatin appears to be equally effective in untreated patients and in those who have progressive disease after splenectomy or after both splenectomy and treatment with interferon. Whether pentostatin is superior to splenectomy or interferon as therapy for hairy-cell leukemia will have to be assessed by direct comparison in randomized studies. Lengthy follow-up will be required to determine a median duration for the responses of hairy-cell leukemia to pentostatin.

Deficient IFN alpha production in hairy cell leukemia.

Since the application of low doses of IFN-alpha is necessary to maintain remissions in Hairy Cell Leukemia (HCL) it is of interest whether peripheral blood mononuclear cells (MNC) of HCL patients can be induced in vitro to produce IFN-alpha. 9 patients suffering from advanced HCL were included in the study. The diagnoses were confirmed by characteristic findings in peripheral blood and bone marrow biopsies. For IFN treatment we initially used natural IFN-alpha (Bioferon) and switched later to recombinant IFN-alpha2 (Boehringer). MNC of 5 patients before IFN therapy and of 6 patients during IFN therapy (2-47 weeks) were induced by phytohemagglutinin (PHA), Corynebacterium parvum (C.p.), and sendai virus (SV). PHA is known to induce IFN-gamma. Both, C.p. and SV induced IFN-alpha but no IFN-gamma in MNC of healthy controls and of IFN treated breast cancer patients. In HCL patients normal antiviral activities could be induced by PHA. Zero or only low antiviral activities could be induced in MNC from 9 patients tested on 22 occasions. It is concluded that MNC from patients with advanced HCL can be induced to produce IFN-gamma but no IFN-alpha. Since IFN-alpha but not IFN-gamma is produced by monocytes it is likely that reduced numbers of monocytes which were found in our HCL patients before and during IFN treatment account for the described deficiency of IFN-alpha production.

Intensive Chemotherapy of Hairy Cell Leukemia in Patients With Aggressive Disease

Seven patients with hairy cell leukemia were treated by intensive chemotherapy because they were considered to have a progressive disease and a poor short-term prognosis. The mean age was 47 years (range, 36 to 58). Six of seven patients had prior splenectomies with minor or transient hematologic responses. One patient had no spleen enlargement. The seven patients had never received any cytotoxic drugs and had prolonged granulocytopenia (less than 300/microL) with recurrent, severe infectious episodes. Chemotherapy included Rubidazone (zorubicine hydrochloride) 450 mg/m2 on day 1, arabinosyl cytosine 200 mg/m2/d from day 1 to day 5, and cyclophosphamide, 2,000 mg/m2 on day 5. Responses were assessed through examination of repeat bone marrow biopsy specimens and blood counts. A complete response was defined as normal blood counts associated with the disappearance of hairy cell infiltration and fibrosis on the bone marrow biopsy specimens. A partial response was defined as normal blood counts with persistence of leukemic cells in the bone marrow. Three patients achieved a complete response, and one patient had a partial response. Three patients died of infectious complications during induction chemotherapy. For the responding patients, the mean duration of aplasia was 37 +/- 5 days. Follow-up for the responding patients has been 44+, 24, 32+, and 23+ months. One patient with a complete response died while on maintenance therapy. We conclude that complete and prolonged histologic remission of hairy cell leukemia can be obtained with intensive chemotherapy. The toxicity of chemotherapy is such, however, that progressive disease after splenectomy needs to be more clearly defined.

Intensive chemotherapy of hairy cell leukemia in patients with aggressive disease

Seven patients with hairy cell leukemia were treated by intensive chemotherapy because they were considered to have a progressive disease and a poor short-term prognosis. The mean age was 47 years (range, 36 to 58). Six of seven patients had prior splenectomies with minor or transient hematologic responses. One patient had no spleen enlargement. The seven patients had never received any cytotoxic drugs and had prolonged granulocytopenia (less than 300/microL) with recurrent, severe infectious episodes. Chemotherapy included Rubidazone (zorubicine hydrochloride) 450 mg/m2 on day 1, arabinosyl cytosine 200 mg/m2/d from day 1 to day 5, and cyclophosphamide, 2,000 mg/m2 on day 5. Responses were assessed through examination of repeat bone marrow biopsy specimens and blood counts. A complete response was defined as normal blood counts associated with the disappearance of hairy cell infiltration and fibrosis on the bone marrow biopsy specimens. A partial response was defined as normal blood counts with persistence of leukemic cells in the bone marrow. Three patients achieved a complete response, and one patient had a partial response. Three patients died of infectious complications during induction chemotherapy. For the responding patients, the mean duration of aplasia was 37 +/- 5 days. Follow-up for the responding patients has been 44+, 24, 32+, and 23+ months. One patient with a complete response died while on maintenance therapy. We conclude that complete and prolonged histologic remission of hairy cell leukemia can be obtained with intensive chemotherapy. The toxicity of chemotherapy is such, however, that progressive disease after splenectomy needs to be more clearly defined.