Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.

Intensive treatment in order to minimize the Ph-positive clone in CML. Danish-Swedish CML Group.

With the rationale that a significant reduction of the malignant clone in CML might prolong time to metamorphosis, intensive treatment was given to patients < or = 55 years. Six months of hydroxyurea and high dose interferon-alpha (IFN-alpha) was followed by one to three courses of intensive chemotherapy. Patients who had a donor were allotransplanted and patients who became Ph-negative in bone marrow were autotransplanted. On 1 May 1995, 160 patients were registered in the study. Fifty-one percent of the patients who received six months IFN-alpha and hydroxyurea had a significant Ph-reduction and 5% became Ph-negative. The corresponding figures after two intensive chemotherapy courses were 47 and 28%, respectively. Twenty-seven of 30 autotransplanted patients have been analysed for Ph. Seventeen have relapsed cytogenetically, while ten are Ph-negative 1-64 + months after ABMT. BMT was performed in 59 patients. The actuarial 6-year survival from diagnosis of all 160 registered patients is 68%, which seems to be better than for age-matched historical controls.

Intensive treatment in order to minimize the Ph-positive clone in chronic myelogenic leukemia.

Several studies indicate that interferon (IFN) treatment, intensive chemotherapy and autologous bone marrow transplantation (ABMT) effectively reduce the Ph-positive clone in Chronic Myelogenic Leukemia (CML). In the present study on patients < or = 55 years, we have combined these three treatment modalities. The aim of the study was to eliminate or minimize the Ph-positive clone to see whether a status of minimal residual or Ph-negative disease could be maintained for a longer period of time. After diagnosis, patients received interferon (IFN-a-2b) and hydroxyurea (HU) to keep the white blood cell (WBC) and platelet count below 2-4 and 100-150 x 10(9)/l, respectively. After six months of treatment, Ph-analysis was performed. Patients with Ph-positive cells in bone marrow then received 1-3 courses of intensive chemotherapy. In patients Ph-negative after two courses, bone marrow was harvested and used for ABMT. After a third course, patients with up to 50% Ph-positive metaphases were accepted for ABMT. As of January 1, 1993, 97 patients were registered in the study. Six months of IFN+HU reduced the percentage of Ph-positive metaphases in 57% of the patients (7% became Ph-negative). The corresponding figures after two intensive cytotherapies were 70% (40% Ph-negative). Eighteen patients were autotransplanted. Seven have relapsed with Ph-positivity 3-22 months after ABMT, while nine are Ph-negative at 1-32+ months after ABMT (two not yet analyzed). Seventeen patients are alive and well, while one died one month after ABMT due to interstitial pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) as outpatient salvage therapy for refractory multiple myeloma.

Fifty-six patients with refractory multiple myeloma were treated with intermittent courses of etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) every 4th week. The overall response rate was 30%. Durable remissions exceeding 1 year were obtained in 12 of the 17 responding patients. A significant prolongation of the survival time was found for responding patients (median 13 months) compared to those patients who did not respond (median 9 months) to EACB therapy (p = 0.01). A low frequency of neutropenic fever episodes was noted compared to other salvage treatment regimens. The EACB regimen was usually well tolerated and could be administered safely on an out-patient basis. This regimen might be an alternative especially for elderly patients unresponsive to initial therapy.

Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden.

Three hundred thirty-five previously untreated patients with multiple myeloma in clinical stages II and III entered a randomized trial comparing intermittent oral melphalan and prednisone (MP) therapy (n = 171) with MP in combination with natural (leukocyte-derived) alpha-interferon (MP/IFN) (n = 164). The treatment groups were comparable with regard to major prognostic factors. The response frequency was 42% in the MP group and 68% in the MP/IFN group (P < .0001). Eighty-five percent of IgA myelomas and 71% of Bence-Jones myelomas responded to MP/IFN compared with 48% and 27%, respectively, to MP treatment (P = .001). There was no difference in the overall survival between the two treatment groups. However, the survival of 72 patients with IgA or Bence-Jones myeloma randomized to receive MP/IFN was significantly longer (median 32 months) than that of 71 patients treated with MP (median 17 months) (p < .05). No statistically significant difference in response frequency (60% v 46%) or survival was found for patients with IgG myeloma. Hematologic toxicity, WHO grades III and IV, was higher in the MP/IFN group (48%) than in the MP group (33%) (P < .05) during the induction treatment period. Flulike syndrome was observed in 68% of patients receiving MP/IFN. The results show that MP/IFN is a well-tolerated treatment regimen, superior to MP for remission induction, and it improves significantly the overall survival for patients with IgA and Bence-Jones myelomas.

Treatment of multiple myeloma with interferon alpha: the Scandinavian experience.

IFN alpha is a biologic therapeutic agent with documented antitumoral effect in multiple myeloma. 15% of previously untreated myeloma patients achieve a clinical response to IFN alpha alone with a possible dose-response relationship. A particularly good effect is noted in IgA myelomas treated with natural IFN alpha. A randomized study was started in April 1986 comparing melphalan/prednisone (MP) therapy with MP plus natural IFN alpha (MP/IFN) in untreated patients with multiple myeloma stages II and III. 220 patients had entered the study by autumn 1989. An interim report is given here. The response frequency was 48% in the MP group and 66% in the MP/IFN group (P less than 0.02). Stage II patients responded better to MP/IFN (76%) than to MP alone (48%) (P less than 0.01). No significant difference was noted for stage III patients. 91% of all IgA myelomas responded to MP/IFN and 52% to MP (P less than 0.01). The difference in response frequency of IgG and BJ myelomas between the two treatment groups was not statistically significant. The observation period is still too short to draw firm conclusions on survival. However, a statistically significant longer response duration time and survival from response (P less than 0.01) was noted for stage II patients.

A 10-year survey of clinically significant blood culture isolates and antibiotic susceptibilities from adult patients with hematological diseases at a major Swedish hospital.

In patients treated with cytotoxic drugs granulocytopenia and septicemia are commonly seen. In this 10-year survey 324 blood culture isolates from 184 patients with hematological diseases and septicemia were studied. The distribution of microbiological diagnoses in patients with hematological diseases as well as acute leukemia 1980-1986 was significantly different (p less than 0.01) from an unselected blood culture material from the same period. The differences are mainly seen between Enterobacteriaceae other than Escherichia coli, Pseudomonas aeruginosa and staphylococci. The microbiological spectrum for patients with hematological disease 1987-1989 was also significantly different (p less than 0.05) from the spectrum of the same group of patients 1980-1986 due to higher frequencies of coagulase-negative staphylococci and alpha-streptococci and lower frequency of E. coli in the latter period. 40% of the isolates were gram-positive cocci during the first period and increased to 50% during the second period. The susceptibility testing indicates that trimethoprim/sulfonamide is not as good a choice as ciprofloxacin or norfloxacin for oral antibiotic prophylaxis. For intravenous therapy imipenem/cilastatin or the combinations of an aminoglycoside/piperacillin or aminoglycoside/third generation cephalosporin have advantages over aminoglycoside/trimethoprim/sulfa in combination. However, addition of isoxazolylpenicillin or vancomycin now seems necessary to cover the increasing part of gram-positive bacteria causing septicemia in patients with hematological disease.

Oral versus intravenous melphalan and prednisone treatment in multiple myeloma stage II. A randomized study from the Myeloma Group of Central Sweden.

Eighty-one previously untreated patients with multiple myeloma stage II entered a randomized trial comparing oral melphalan (0.25 mg/kg/day; n = 40) with intravenous melphalan (0.125 mg/kg/day; n = 41) in combination with oral prednisone (2 mg/kg/day). The courses were given for 4 days and repeated every sixth week. The treatment groups were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, the response duration times and the survival times. No significant difference in nonhematological and hematological toxicity was noted. Since intravenous administration of melphalan did not result in a substantial increase in response rate or survival, this study supports the use of oral melphalan/prednisone as first-line therapy for patients with multiple myeloma.

Alternating combination chemotherapy (VMCP/VBAP) is not superior to melphalan/prednisone in the treatment of multiple myeloma patients stage III--a randomized study from MGCS.

86 previously untreated patients with multiple myeloma stage III entered a randomized trial comparing combination chemotherapy (VMCP/VBAP) (n = 42) with intermittent oral melphalan and prednisone (MP) treatment (n = 44). The treatment gropus were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, 52% (VMCP/VBAP) vs 61% (MP); in the response duration times, median 19 months vs 22 months, or in the survival times, median 24 months vs 28 months. However, survival of patients older than 65 years was significantly shorter in the VMCP/VBAP group (median 15 months) compared to the MP group (median 23 months) (p = 0.03). No significant difference in non-hematological or hematological toxicity was noted. The study further supports the notion that MP therapy should be used as primary standard treatment for patients with multiple myeloma.

Induction treatment with alpha-interferon in multiple myeloma: an interim report from MGCS.

A randomized study comparing melphalan/prednisone (M/P) therapy with MP + natural alpha-IFN in untreated patients with multiple myeloma stages II and III started April 1, 1986. By March 1989, 78 patients were evaluable in the MP group and 80 in the MP/IFN group. 48% of the MP patients achieved a response and 66% in the MP/IFN group (p = 0.04). Stage II patients responded better to MP/IFN (76%) than MP alone (47%) (p = 0.02), while no statistically significant difference was noted for stage III patients. 90% of the IgA myelomas responded to MP/IFN and 52% to MP (p = 0.02). Both for IgG and BJ myelomas the response rates of MP/IFN were higher than of MP, although the differences were not statistically significant. The observation period is still short. There was no difference in total survival between the two treatment groups. However, in patients less than or equal to 65 years a tendency to a longer survival was seen for those receiving the IFN combination (p = 0.12).