Immunotherapy for acute myelogenous leukaemia: a controlled clinical study 2 1/2 years after entry of the last patient.

One hundred and thirty-nine untreated patients with acute myelogenous leukaemia (AML) were admitted between August 1970 and December 1973 and allocated into two remission treatment regimens: one to receive chemotherapy alone and the other chemotherapy with immunotherapy. Of the patients who attained remission. 22 were in the chemotherapy group and in September 1975 2 remained alive, the median survival time being 270 days and after relapse 75 days. Twenty-eight patients received immunotherapy during remission, and 5 remained alive; the median survival time of the group being 510 days and after relapse 165 days. Ongoing acturial analysis precisely predicted early in the study the median survival of the two groups, but it took a 2-year follow-up after entry of the last patient before it became clear that there were very few long-term survivors. The increase in survival time produced by the immunotherapy is apparently made up of two components: prolongation of the first remission and length of survival after the first relapse. It must be notted that the chemotherapy for this study was devised 6 years ago and the results of the control arm (chemotherapy alone) may be poorer than those obtained in contemporary studies.     

Treatment of relapsed and refractory acute leukaemia with high-dose cytosine arabinoside and etoposide

Summary A total of 65 patients under the age of 55 with acute leukaemia received high-dose cytosine arabinoside (Ara-C) in combination with high-dose etoposide without an anthracycline. Complete remission rates for patients with relapsed or refractory acute myelogenous leukaemia (AML) were 15/25 (60%) and 11/16 (69%), respectively. The complete remission rate for patients with refractory or relapsed acute lymphoblastic leukaemia (ALL) was 10/18 (56%). The treatment-related mortality was 17%. Nine patients whose leukaemia relapsed after matched allogeneic, sibling bone-marrow transplantation (BMT) were also treated in this way; the treatment-related mortality in this group was high (7/9) and the duration of remission in the two patients who responded, too short to justify this intensive treatment in such patients. Similarly, patients who underwent BMT after achieving a complete remission with high-dose Ara-C and etoposide did very poorly, only one patient surviving well and disease-free at 8 months. The important finding in this study was the high complete remission rate rapidly obtained in patients with relapsed or refractory AML without using an anthracycline.     

The maintenance of busulphan-induced remissions in chronic granulocytic leukaemia with recombinant interferon alpha-2b

Interferon (IFN) shows no specificity in inhibiting the growth of colonies of myeloid leukaemia blasts in culture as compared to normal haemopoietic precursors, but does reduce the self-renewal capacity of myeloblasts. We have tested the ability of IFN to slow the leukocyte doubling time (Ldt) and to prolong remissions induced by busulphan in 14 patients with chronic granulocytic leukaemia (CGL). Patients served as their own controls; the Ldt during relapse from a busulphan-induced remission on no therapy was determined and compared with the Ldt on IFN maintenance therapy. The initial dose of IFN (2 x 10(6) U M-2 subcutaneously, three times per week) was adjusted up, or down, to prevent the leukocyte count from rising and the platelet count from falling below 75 x 10(9) l-1. The dose of IFN required to prevent relapse in seven patients ranged from 1 x 10(6) U M-2 three times per week to 5.2 x 10(6) U M-2 daily, with a median of 2 x 10(6) U M-2 three times per week. IFN maintenance therapy has prevented relapse in six patients for more than 22 months to more than 68 months. In five patients the Ldt was slowed initially but the disease later progressed in four patients to enter the accelerated (three patients) or blast phase (one patient). The Ldt during IFN therapy did not change from the Ldt on no therapy in one patient; this patient later progressed to the blast phase. In two additional patients the leukaemia progressed during the first course of IFN, with shortening of the Ldt; both of these patients entered the blast phase. In the four patients who have discontinued IFN following relapse in the chronic phase, the Ldt remained prolonged for at least one relapse after the IFN was stopped. IFN maintenance therapy failed to control the leukocyte count in the six patients with a control Ldt of less than 40 days and five of these have progressed to enter the accelerated or blast phase. The early survival of this group of patients resembles the survival of 'good risk' CGL patients reported by others. We conclude that IFN maintenance therapy does alter the relapse pattern of a subset of CGL patients, either slowing the Ldt or preventing relapse.     

Early allogeneic transplantation for refractory or relapsed acute leukaemia following remission induction with FLAG.

The prognosis for patients with secondary AML, primary resistant AML or ALL and early (<12 months) relapse of acute leukaemia remains extremely poor with conventional chemotherapy. As part of a strategy to improve the outcome for these patients we have treated 22 consecutive patients (18 AML, four ALL, median age 35 years) with either primary resistant disease (n=3), early relapsed leukaemia (n= 12) or secondary AML (n= 7, four RAEBt, two antecedant ALL and one antecedant Hodgkin's disease) with 'FLAG' induction chemotherapy with the aim of proceeding to early allogeneic transplantation either from sibling or unrelated donors. Eighteen patients achieved CR after one course of FLAG, including five patients who had documented p-glycoprotein-induced multidrug resistance and 10 patients with adverse cytogenetic abnormalities. Eight patients were consolidated with a second course of FLAG prior to transplantation and so far 16 patients have undergone allogeneic transplantation, 10 from unrelated donors and six from sibling donors (one mismatched). By the time of transplant three patients had progressed and were in early relapse and all have relapsed post BMT. Of the remaining 13 patients transplanted in remission, nine remain in CCR at a range of 4-26 months, three have died of transplant-related complications (18%) and one patient has relapsed. We conclude that the use of FLAG induction therapy followed by early allogeneic transplantation from either a sibling or unrelated donor can be an effective strategy for the treatment of this difficult group of young patients with poor risk acute leukaemia and appears to be associated with a low procedure-related risk.     

Cisplatin-based chemotherapy in primary central nervous system germ cell tumors

We report a retrospective review of our experience with cisplatin-based chemotherapy in eight patients (ages 9–44 years) with histologically confirmed primary central nervous system germ cell tumors. Five patients received chemotherapy as the primary treatment, radiation therapy being administered either at completion of chemotherapy or between chemotherapy courses. Three patients received cisplatin-based chemotherapy for recurrent disease after prior radiation therapy and/or surgery. Four of five patients treated with chemotherapy at diagnosis are in complete remission at 11–14 months from diagnosis. The remaining patient twice achieved complete remission prior to dying of progressive disease 16 months after diagnosis. Two of three patients treated with chemotherapy for recurrent disease are in complete remission at 20 and 26 months; the remaining patient deteriorated after the first cycle of chemotherapy and expired six months thereafter. Overall, of seven patients evaluable for response, five achieved complete remission with chemotherapy alone, and two with chemotherapy and radiation therapy. Our results confirm previous reports of high complete remission rates utilizing cisplatin-based chemotherapy in conjunction with radiation therapy. Prospective evaluation of cisplatin-based chemotherapy followed by radiation therapy is warranted.     

The impact of total body irradiation on the outcome of patients with follicular lymphoma treated with autologous stem-cell transplantation in the modern era: a retrospective study of the EBMT Lymphoma Working Party

BackgroundThe aim of this study was to investigate the impact of the high-dose regimen on the outcome of patients with follicular lymphoma (FL) having had autologous stem-cell transplantation (ASCT) in a recent time period.PatientsBetween 1995 and 2007, 2233 patients with FL had their first ASCT with either a total body irradiation (TBI)-containing regimen or carmustin, etoposide, cytarabine and melphalan (BEAM), of which 47% were autografted in first remission.ResultsAfter a median observation time of 73 months (interquartile range 30–107), 5- and 10-year non-relapse mortality (NRM) was similar (6% and 10% in both groups). No significant NRM differences became evident after multivariate adjustment for confounders. Secondary malignancies were observed in 9.7% and 7.9% of the patients after TBI and BEAM (P = 0.19), which were treatment-related myelodysplastic syndromes/acute myelogenous leukaemia (t-MDS/AML) in 3.4% and 2.8% (P = 0.57). The median time to t-MDS/AML was around 50 months in both groups. Because of a lower relapse incidence, TBI was associated with better event-free survival reaching statistical significance in the patients transplanted in first remission but not in those transplanted beyond first remission.ConclusionsIn patients with FL who received TBI-based ASCT after 1995 increased NRM and t-MDS/AML risks did not emerge compared with BEAM while disease control was at least equivalent.     

Abnormalities of chromosome 16q in myeloid malignancy: 14 new cases and a review of the literature.

Fourteen patients with abnormalities of chromosome 16q, 13 with acute myelogenous leukaemia (AML), and one with refractory anaemia with excess of blasts (RAEB), are described. Seven patients had inv(16)(p13q22), two had del(16)(q22), and five had other abnormalities of 16q. Six of the seven patients with inv(16) had AML M4Eo and, following treatment with adriamycin, cytosine arabinoside, and 6-thioguanine, all achieved complete remission (CR). Neither patient with del(16)(q22) had typical M4Eo morphology at diagnosis; CR was achieved in one and one had resistant leukaemia. Patients with other abnormalities of 16q had blasts of diverse morphology and, although morphologically abnormal eosinophils were seen in three patients, this was not as marked as in the patients with inv(16). CR was achieved in two of the four patients with other abnormalities of 16q but duration of remission was short in both cases. These results suggest that most patients with del(16)(q22) and other abnormalities of 16q22 do not have typical AML M4Eo. Such patients tend to have a worse prognosis, and are more likely to have complex karyotypes typical of secondary leukaemia.     

Refractory acute lymphocytic leukemia: Response to aclacinomycin a and VP-16-213

Twelve patients with acute lymphoblastic leukemia (ALL) were treated with aclacinomycin A (60 mg/m²/day for five days) and VP-16-213 (100 mg/m²/day). All were heavily pretreated and had relapsed or were refractory to primary or subsequent treatment. Eight patients were refractory to reinduction therapy given for first, second, third or fourth relapse. One patient was treated in third relapse; one in second relapse (after a short second remission) and two in first relapse—one with the Ph¹ chromosome, after a four-month remission, and one patient who relapsed while receiving consolidation therapy. Four patients (33 per cent) responded, three entered complete remission (25 per cent), and one a partial remission (8 per cent). Two of the patients treated for refractoriness to reinduction therapy went into complete remission. Side effects from this treatment were similar to the conventional DAT regimen (daunorubicin, cytosine arabinoside, thioguanine), although the gastrointestinal toxicity and mucositis appeared to be more severe in this study population. One of the patients had severe ventricular arrhythmias which contributed to her death. The complete remission rate (25 per cent) in this group of very heavily pretreated ALL patients warrants further studies to evaluate these preliminary findings.     

VAD chemotherapy--toxicity and efficacy--in patients with multiple myeloma and other lymphoid malignancies

Thirty-three patients with multiple myeloma (11 untreated, 15 refractory and seven relapsed patients) have received vincristine and adriamycin infusion therapy with oral dexamethasone (VAD). The median number of course received was five. In addition 16 patients with lymphoid malignancy have received a median of four courses of VAD. Three patients who relapsed after VAD have received further VAD therapy making 52 patient treatments assessable for toxicity. Ten per cent had nausea, 4 per cent vomiting, 4 per cent total alopecia, 25 per cent constipation, 33 per cent paraesthesiae, 8 per cent proximal myopathy, 33 per cent dyspepsia, 23 per cent proven bacteraemia, and 19 per cent chest infections. Infections were not usually associated with neutropenia. Shingles was seen in four patients with myeloma, but none of the patients with lymphoid malignancy. The response rate in myeloma was 9/11, for previously untreated patients, 3/7 for relapsed, and 8/15 for refractory patients. Responses have been seen in other lymphoid malignancies-1/2 patients with relapsed acute lymphoblastic leukaemia had a complete remission. Two out of seven patients with chronic lymphocytic leukaemia achieved a partial remission, and a further three had a clinical improvement. Three out of six patients with non-Hodgkin lymphoma and one patient with macroglobulinaemia achieved a partial remission.     

Therapeutic use of interferon-alpha for lymphomatoid papulosis

BACKGROUND: Lymphomatoid papulosis is a primary cutaneous, CD30 positive lymphoproliferative disorder with the potential to transform into systemic, malignant lymphoma. Therapeutic strategies for patients with lymphomatoid papulosis have been designed to prevent transformation but have proved to be either inefficacious or limited by side effects. METHODS: The authors compared the clinical, histologic, and immunohistochemical features from a group of five patients receiving interferon-alpha (IFN-alpha) subcutaneously three times per week with the same features from a group of six patients receiving conventional therapy, including photochemotherapy, antibiotics, topical corticosteroids, or surgery, in an open trial. RESULTS: In the IFN-alpha group, four patients showed a complete remission, and one patient showed a partial remission within a time period of 6 weeks. Two patients developed disease recurrences after discontinuation of short term IFN-alpha therapy (5-7 months). Thereof, one patient went into stable remission after long term IFN-alpha therapy (17 months), and one patient remains in partial remission. In the control group, one patient went into spontaneous remission, two patients showed partial remission, of which one patient developed progressive disease at a later time point, whereas three patients have recurrent disease despite of treatment. CONCLUSIONS: The current results indicate that the treatment with IFN-alpha of patients with lymphomatoid papulosis alters the clinical course of the disease with fewer side effects than previous regimens; however, short term treatment does not induce stable remission. Therefore, prolonged treatment appears to be warranted for these patients.     

A unique case of three autografts for acute myelogenous leukaemia with subsequent long term survival in second remission

We report here a patient with acute mycloid leukaemia who relapsed 20 months after undergoing a double autograft procedure in first remission. He was reinduced and subsequently underwent a third autologous bone marrow transplantation in second remission using bone marrow harvested in second remission and a Busulphan and Cyclophosphamide conditioning regimen. Although the engraftment was very slow, he has remained in second remission for 34+ months. This case demonstrates that durable disease-free survival can be attained by a second preparative therapy, even in second remission, for patients relapsed after autologous bone marrow transplantation.     

A phase II open‐label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome

Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m² via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55–84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate‐1, five intermediate‐2 and two high‐risk. Median chemotherapy courses were one (1–3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction – from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non‐haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35–72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS.     

Immunotherapy for acute myelogenous leukaemia

One hundred and seven untreated patients with acute myelogenous leukaemia (AML) were admitted to St Bartholomew''s Hospital between 10 October 1970 and 31 January 1973. Before receiving drugs to induce remission they were allocated alternatively into 2 groups to decide their remission treatment—a group to receive chemotherapy alone and a group to receive the same chemotherapy with immunotherapy. The patients were then given induction chemotherapy and 45 of them attained complete remission. All patients in remission then received chemotherapy consisting of 5 days treatment every 28 days. Patients receiving immunotherapy were also given multiple weekly intradermal injections of irradiated stored AML cells and Glaxo B.C.G. using a Heaf gun. There were 19 patients in the group which received only chemotherapy during remission; 7 of these patients remain alive (median survival after attaining remission 303 days) and only 5 are still in their first remission (median remission length 188 days). Twenty-three patients were allocated to receive immunotherapy during remission in addition to chemotherapy and 16 remain alive (median 545 days) and 8 are in their first remission (median 312 days). The difference in survival of the two groups is significant with a P value of 0·003.     

A Unique Case of Three Autografts for Acute Myelogenous Leukaemia with Subsequent Long Term Survival in Second Remission

We report here a patient with acute mycloid leukaemia who relapsed 20 months after undergoing a double autograft procedure in first remission. He was reinduced and subsequently underwent a third autologous bone marrow transplantation in second remission using bone marrow harvested in second remission and a Busulphan and Cyclophosphamide conditioning regimen. Although the engraftment was very slow, he has remained in second remission for 34+ months. This case demonstrates that durable disease-free survival can be attained by a second preparative therapy, even in second remission, for patients relapsed after autologous bone marrow transplantation.     

Pentostatin in refractory chronic lymphocytic leukemia: a phase II trial of the European Organization for Research and Treatment of Cancer

Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment. Twenty patients had progressive disease on previous regimens and six had had partial remission and then relapsed 3-34 months after previous chemotherapy. Eleven patients had previously been treated with three different regimens. 10 had been treated with two regimens, and five had been treated with one regimen. Pentostatin was administered at a dosage of 4 mg/m2 weekly for 3 weeks, then 4 mg/m2 every other week for 6 weeks and once a month for 6 months. Seven of 26 assessable patients (27%) achieved partial remission and five (19%) achieved clinical improvement. The median duration of partial remission until relapse or death was 210 days. Myelosuppression was minor and transient in responsive patients, indicating some degree of selective effect on lymphocytes. Except for one patient who died of cerebral hemorrhage during the first 6 weeks of treatment, no drug-related deaths were registered. Major toxic effects included nausea in 17 patients (mainly grade 1), infections in 15, and liver enzyme elevations in five. Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens. Response can be achieved with mild myelosuppression.     

Use of logistic regression analysis to improve prediction of prognosis in acute myeloid leukaemia

The prognostic usefulness of a range of factors has been examined for patients with acute myeloid leukaemia. Although there was a statistical association between some of these factors and remission rate, the association was only partial. To improve the usefulness of the data, multiple logistic regressional analysis was used. The features selected for use in the analysis were age, blood blast count, FAB classification and colony growth pattern. The last three features could be used as categorical variables, since blood blast counts of greater than 100 X 10(9)/1, FAB group 1 and a prolific pattern of colony growth were associated with a low remission rate. Age was used as a continuous variable. Using these features, eight regression groups were defined. Thus when this data for an individual patient is analysed, it is possible to obtain a value for the probability of that patient achieving remission.     

Etoposide and cytosine arabinoside combination chemotherapy for refractory acute lymphocytic leukemia in childhood

Eighteen children with refractory acute lymphocytic leukemia (ALL) who had been heavily pretreated, were treated with combination etoposide and cytosine arabinoside (ara-C) chemotherapy. Seventeen of these 18 patients were in their first to third relapses; the remaining patient had never responded to induction therapy. The drug combination of etoposide followed by ara-C was administered as an intravenous (IV) infusion twice a week for two consecutive weeks, a total of four doses. The dosage was 150 mg/m2/dose for each drug. Seven (39%) of the 18 patients attained a complete remission (CR) and three (17%) attained a partial remission (PR). Complete response was obtained in two of eight patients in first marrow relapse, and in five of nine patients in second and third relapse. Five patients achieved a CR after one course of therapy and two achieved a CR after two courses of therapy. Of three patients who had previously received teniposide, two attained a CR with this combination. The duration of these responses was brief with a median of 1 month, ranging from 0.5 to 3 months, with the exception of one case, which has been in remission for 2.5 + months. Although myelosuppression was observed, none of the patients died from infection or bleeding. Allergic reaction with fever and rash was observed in two patients. The efficacy of the etoposide and ara-C combination for refractory childhood ALL is encouraging in several current reinduction regimens.     

High-dose melphalan and autologous bone marrow transplant for relapsed acute leukaemia

Summary Seven patients with relapsed acute leukaemia were treated with high-dose melphalan (HDM) followed by the infusion of autologous cryopreserved remission marrow. Toxicy was minimal and all seven patients had a complete response. Four patients are still in unmaintained remission at 14, 13, 10, and 3 months, the first two having received a second course of HDM to consolidate the result. The role of HDM as a form of intensification therapy for patients with acute myeloid leukaemia in first remission should be investigated.     

The efficacy and safety of Epstein-Barr virus-specific antigen peptide-activated cytotoxic T-cells treatment for refractory or recurrent angioimmunoblastic T-cell lymphoma: A prospective clinical observational study

The efficacy and safety of Epstein-Barr virus (EBV)-specific antigen peptide-activated cytotoxic T lymphocytes (CTLs) in the treatment of refractory or recurrent angioimmunoblastic T-cell lymphoma (AITL) was determined in this prospective one-arm clinical study. Seven males and two females were enrolled with a median age of 70 years. The tumor stages were all stage III and IV. All patients had group B symptoms and IPI scores of 3 to 5 points. All patients received chemotherapy before CTLs infusion which the median chemotherapy cycle was three. The diseases states before CTLs included five cases of disease progression (PD), two cases of recurrence (R), and two cases with residual lesions after chemotherapy. Eight patients received HLA-haploidentical EBV-specific CTLs, and one patient chose autologous CTLs. The number of transfused cells was 1.67 to 2.38 × 10¹⁰ for one course of CTLs therapy. One patient was treated with three courses of CTLs, three patients were treated with two courses of CTLs, and five patients were treated with one course of CTLs. During the infusion, eight patients had fever, one patient had rash, and no graft-vs-host diseases were observed. The EBV-DNA decreased by more than two orders of magnitude in six patients, and the response rate was 66.7%. Two patients of PD status achieved complete remission (CR), one patient of PD status achieved partial remission, two patients with residual lesions after chemotherapy achieved CR, and four patients had no response. The objective remission rate was 55.6%. After the median follow-up of 14.5 months, five patients died, and three patients were completely relieved while one patient was lost during follow-up. The 3-year overall survival was 44.4% and 3-year progression-free survival was 33.3%. EBV-specific antigen peptide-activated CTLs showed positive effect in certain patients with refractory and recurrent AITL with high clinical safety.     

Adult acute leukaemia

Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML) or acute undifferentiated leukaemia (AUL). The periodic acid-Schiff stain was of little value in differentiating the 3 groups. The treatment response in each group was different: 94% of patients with ALL (16/17) achieved complete remission with prednisone, vincristine and other drugs in standard use in childhood ALL; 59% of patients with AML (27/46) achieved complete remission with cytosine arabinoside and daunorubicin (22 patients), or 6-thioguanine and cyclophosphamide (2 patients), 6-thioguanine, cyclophosphamide and Adriamycin (1 patient), and cytosine and Adriamycin (1 patient); only 2 out of 14 patients (14%) with acute undifferentiated leukaemia achieved complete remission using cytosine and daunorubicin after an initial trial of prednisone and vincristine had failed. Prednisone and vincristine would seem to be of no value in acute undifferentiated leukaemia. It would seem also that no benefit is obtained by classifying all patients with acute leukaemia over 20 years of age as “adult acute leukaemia” and treating them with the same polypharmaceutical regimen. The problems posed by each disease are different and such a policy serves only to obscure them.