M. J. Barnett

Chlorambucil and interferon for low grade non-Hodgkin's lymphoma

Despite responsiveness to both chemotherapy and radiation therapy, most patients with low grade non-Hodgkins lymphoma (NHL) die as a consequence of the disease. Chlorambucil (CB) alone yields responses in approximately seventy-five percent of patients with a median duration of first remission of one to two years. However, although subsequent remissions can often be achieved, the characteristic continuous relapse pattern results in a median survival of between five and ten years (Jones et al., 1973; Young et al., 1977; Lister et al., 1978; Rudders et al., 1979; Hoppe et al., 1981; Anderson et al., 1982; Gallagher et al., 1986). It has been demonstrated that administration of leucocyte or recombinant DNA interferon causes regression of disease in approximately forty per cent of patients with low grade lymphoma (Merigan et al., 1978; Louie et al., 1981; Ozer et al., 1983; Horning et al., 1985; Wagstaff et al., 1986). Combinations of interferon with conventional cytotoxic agents have been investigated in murine models of leukaemia and lymphoma (Chirigos & Peason, 1973; Gresser et al., 1978; Slater et al., 1981; Tozawa et al., 1982; Mowshowitz et al., 1982); longer survival was observed in animals receiving the combination than in those receiving either drug alone. On the basis of these observations it was decided to investigate the concurrent administration of CB and interferon (IFN-a2) in previously treated patients with low grade NHL. Twenty-three patients (median age 52 years, range 28-70) with recurrent, low grade NHL (11 follicular, 6 centrocytic, 4 lymphoplasmacytoid, I peripheral T cell) and 1 patient with chronic lymphocytic leukaemia received CB and IFN-ac2 as shown in Figure 1. All, except one patient with follicular lymphoma had bone marrow infiltration at the time of treatment.

Short-term therapy for acute myelogenous leukemia.

Since 1978, 187 patients (age range, 15 to 59, median 44 years) have received short-term chemotherapy as part of three sequential open studies (B-IX, X, Xb) or a randomized clinical trial (B-XI). An intended six cycles of Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), cytarabine (ara-C), and thioguanine (TG) were administered with as short an intercycle time as possible. No further therapy was administered. Complete remission (CR) was achieved in 118 of 187 patients (63%). On univariate and multivariate analyses achievement of CR correlated adversely with a low serum albumin at presentation and an antecedent marrow disorder. Forty-five patients continue in first remission between 15 months and 8 1/2 years, no relapses being seen after 3 1/2 years (median follow-up, 3 1/2 years). The median duration of remission was 1 year. M3 morphology, a blast count less than 100 x 10(9)/L, and absence of hepatosplenomegaly correlated favorably with remission duration. There was no difference in duration of remission between patients receiving 3, 4, 5, or 6 cycles. The best results overall were achieved in patients under the age of 40, with 43% projected to remain free of disease at 5 years. Fifty patients remain alive between 17 months and 9 years, the predicted actuarial survival being 25% at 5 years.

The treatment of acute myelogenous leukemia.

It has recently been suggested that it is possible to cure at least 25% of younger adults who have acute myelogenous leukaemia [1], The results achieved at St. Bartholomew’s Hospital, London, demonstrate this and may be used to illustrate the still outstanding problems.

A randomized trial comparing vindesine and cisplatinum to vindesine and methotrexate in advanced non small cell lung carcinoma

Combination chemotherapy using vindesine and cisplatinum has been reported to be active in non-small cell lung carcinoma (NSCLC). In an attempt to reduce the potential neurotoxicity of this combination, and to assess the role of cisplatinum, a randomized trial has compared vindesine and cisplatinum to vindesine and methotrexate in 48 patients with advanced symptomatic NSCLC. Patient characteristics were similar in the two treatment arms. Objective tumour response and survival were similar for both treatments. No complete response occurred. Four patients receiving vindesine/cisplatinum (16%) and three patients receiving vindesine/methotrexate (13%) had a partial response. All responses occurred in patients with a performance status of 70% or more and no response was seen in patients with squamous cell carcinoma. Median survival for both regimens was 16 weeks. Toxicity was considerable and only six patients (12.5%) felt better on treatment. Nausea and vomiting were more frequent in the vindesine/cisplatinum arm, but mild neurotoxicity was more common in the vindesine/methotrexate arm. The low response rates, short survival and significant toxicity suggest that the role of combination chemotherapy in NSCLC remains to be established.

Intensive chemotherapy for acute lymphoblastic leukaemia in adults

High-dose cytosine arabinoside (HD Ara-C) has been shown to induce complete remission in acute lymphoblastic leukaemia (ALL) which is refractory to, or which has recurred following conventional therapy [1–5]. This study was undertaken to determine whether the incorporation of HD Ara-C at a dose of 2 g/m2 twice daily for 6 days into the treatment previously used at St. Bartholomew’s Hospital (OPAL) [6] would improve the prognosis of adults with ALL.

In Vitro Treatment of Bone Marrow from Patients with T-Cell Acute Lymphoblastic Leukemia and Non-Hodgkin’s Lymphoma Using the Immunotoxin WT1-Ricin A

The murine monoclonal antibody WT1 [1] identifies a glycoprotein of molecular weight 40000 present on normal thymocytes and blasts from patients with T-cell acute lymphoblastic leukaemia (T-ALL) [2]. The antibody may be linked by a disulphide bond to the A chain of ricin [3] to form an immunotoxin (WT1-ricin A) which kills cells that express the WT1 antigen but does not have an inhibitory effect on haematopoietic precursors [4].

The Feasibility of Opal/High Dose Ara-C Treatment of Adult Acute Lymphoblastic Leukaemia

Studies conducted at St. Bartholomew’s Hospital between 1972 and 1982 into the treatment of acute lymphoblastic leukaemia (ALL) in adults showed a complete remission (CR) rate of 65% (73/112) using a combination of vincristine, prednisolone, adriamycin, and L-asparaginase, with CR frequency being highest in young patients and lowest in those with L3 morphology. The duration of remission correlated closely with blast cell count at presentation and the surface phenotype of the blast cells, being significantly longest in patients with low blast counts of common ALL antigen (CALLA) positivity. Central nervous system (CNS) relapse alone was relatively frequent in those patients in whom the cerebrospinal fluid (CSF) was positive at the first lumbar puncture (3/13) despite craniospinal or cranial irradiation and intrathecal therapy. However, by far the greatest problem was bone marrow relapse alone, or in association with relapse at other sites, e. g. CSF, testis, skin (43/53) and was not reduced by introducing escalating doses of adriamycin and cyclophosphamide into the early therapy [1].