Seroprevalence of Helicobacter pylori infection in patients with lymphoma.

To determine the Helicobacter pylori (HP) seroprevalence in patients with non-Hodgkin's lymphoma (NHL) and other hematological conditions. Sera were collected from 444 patients with NHL, Hodgkin's disease (HD), lymphoproliferative disorders (LPD), myeloproliferative disorders (MPD), and other hematological conditions. HP seropositivity was determined by ELISA and the results were compared among diagnostic groups HP seropositivity was observed in 168/444 (38%) of the total population. Higher seropositivity rates were associated with increasing age (p=0.001), and country of birth outside the USA and Canada (p=0.0001). Among the diagnostic groups, patients with NHL demonstrated the highest frequency (43%) and those with HD, the lowest frequency (20%; p=.026) of HP seropositivity. The differences among diagnostic groups remained statistically significant after controlling for country of birth (p<0.05), but not after controlling for patient age at diagnosis. The HP seroprevalence of G1 NHL was 55% compared to 40% for non-G1 NHL (p=NS). The highest rate of HP seropositivity (67%) occurred in gastric MALT lymphoma patients, although this did not reach statistical significance compared to the non MALT group (50%) due to small sample size. In conclusion, the rate of HP seropositivity in patients with MALT lymphoma in the USA appears to be lower than in Europe. Helicobacter pylori does not appear to be an important factor in other types of NHL of the G1 tract or elsewhere. Studies of HP prevalence should be controlled for country of birth as well as for age.

Sequential mitoxantrone, daunorubicin, and cytosine arabinoside for patients with newly diagnosed acute myelocytic leukemia.

Mitoxantrone (M) is a synthetic aminoanthraquinone with anti-leukemic activity in patients with daunorubicin (D) resistant acute leukemia. The Cancer and Leukemia Group B (CALGB) has undertaken a limited access pilot study in which M, 12 mg/m2, over 30 min, daily for 3 days, and cytosine arabinoside (Ara-C), 100 mg/m2/day by constant infusion for 7 days were used for the induction of newly diagnosed patients with AML. Responding patients were consolidated with daunorubicin, 45 mg/m2/day for 3 days, and 7 days of Ara-C. After a second consolidation identical to induction, no further therapy was given. Twenty-nine patients with a median age of 50 years (range 18-72) were entered in the study; 18 were males and 11 females. Twenty-four (83%) patients achieved CR, 1 patient achieved a PR, and 4 died in induction from leukemia-related causes. Two patients died in CR from consolidation-related neutropenic sepsis and two additional patients died in CR. Of 24 patients, 7 remain disease-free at a median follow-up interval of 8 years. The regimen is active and well tolerated. The duration of disease-free survival in responding patients is consistent with that seen in similar regimens using intensification chemotherapy without prolonged maintenance.

Increased incidence of HLA antigen B35 in patients with chronic lymphocytic leukemia.

We and others have reported an increased incidence of chronic lymphocytic leukemia (CLL) among Ashkenazi (ASH) Jews of European origin. We performed HLA Class I typing on all 50 CLL patients seen by us and compared them with 3886 controls consisting of healthy blood donors from the New York Blood Center. Thirty of our CLL patients were ASH Jews, 17 of whom (57%) expressed the B35 antigen compared with 462 ASH controls (26%). Seven (39%) of the CLL Caucasian patients expressed the B35 antigen compared with 305 (14.5%) of the Caucasian controls. Combining the information from the ASH Jews and the Caucasians the difference is highly significant, (p = 0.0001). The summary odds ratio was 3.7. These results indicate an increased incidence of the antigen B35 amongst ASH and Caucasian patients with CLL.

Increased incidence of hematologic malignancies in first-degree relatives of patients with chronic lymphocytic leukemia.

Cases of leukemia in more than one family member occur rarely. Family members of patients with chronic lymphocytic leukemia (CLL) may, however, be at increased risk of hematologic malignancy. The charts of all patients with CLL (29) seen by the author from 1987 through 1989 were reviewed and living patients specifically questioned about family history of malignancy. Ten of the 29 (34%) had a first-degree relative with a hematologic malignancy. Three patients had a first-degree relative with CLL including a pair of identical twins. Two additional patients had a spouse with a lymphoid malignancy. No differences were found in serum immunoglobulin levels between those patients with a family history of hematologic neoplasia and those without. The lymphocytes of the majority of patients with a family history of hematologic neoplasia (60%) expressed kappa light chains as did those without (70%). An increased incidence of lymphoid malignancy has been reported in western Ashkenazi Jews and in particular those of Russian descent. The majority of our cases were of Jewish origin and came from Eastern Europe. Seven of 10 patients with a family history of hematologic neoplasia were from Eastern Europe. In contrast only one of three patients with CLL who had a first-degree relative with CLL was of Jewish origin.

The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B.

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.

Protein C and S levels in acute leukemia.

Patients with acute leukemia undergoing remission induction chemotherapy occasionally develop venous thrombosis despite severe thrombocytopenia and in the absence of disseminated intravascular coagulation. This observation prompted us to study the levels of the naturally occurring anticoagulant proteins C and S prospectively in patients undergoing remission induction chemotherapy for acute leukemia. Plasma samples from 50 adult patients with acute leukemia (34 AML, 16 ALL) were analyzed for protein C antigen, functional protein C, immunologic total and free protein S as well as levels of C4b binding protein (C4bBP). Plasma levels of immunologic protein C were significantly lower in patients with active acute myelocytic leukemia (mean = 77.9) than in controls (mean = 123.6) or patients in remission (mean = 132). Functional protein C levels were also significantly lower in AML patients with active disease (mean = 58.5) than controls (mean = 95.5) or patients in remission (mean = 98.5). Patients with acute lymphocytic leukemia (ALL) had normal levels of immunologic and functional protein C. Although total protein S levels were normal in all patients studied, levels of free protein S were significantly decreased in patients with active AML (mean = 29.3) compared with patients in remission (mean = 42.0) or controls (mean = 42.4). In contrast, patients with ALL, both with active disease and in remission had normal free protein S levels. This decrease in free protein S seen in active AML was not associated with liver disease, white cell count or an increase in C4bBP. These findings provide a possible explanation for the occasional occurrence of venous thrombosis in patients with acute myelocytic leukemia.

Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study.

This paper reports a study of the Cancer and Leukemia Group B (CALGB) comparing daunorubicin (DNR) or mitoxantrone (DHAD) in induction followed by multidrug intensification over 8 months in adult patients with acute lymphocytic leukemia (ALL). A total of 164 newly diagnosed patients were randomly assigned to either DNR or DHAD plus vincristine, prednisone and methotrexate given intravenously (i.v.) and interthecally (i.t.). Patients received four more intensification courses of chemotherapy and then all therapy was stopped. Central nervous system (CNS) prophylaxis consisted of nine infusions of intermediate dose methotrexate (MTX) and intrathecal MTX. DHAD and DNR were equally effective in producing complete remissions (63 and 65%, respectively). The estimated median remission duration is 10.2 and 12.3 months for the DHAD and DNR arms, respectively (p = 0.56). This study was stopped earlier than planned when it became apparent that remission duration for both arms was shorter than seen in our prior study in which all patients received more than 1 year of maintenance therapy. The estimated median survival is 18.3 and 20.6 months for the DHAD and DNR arms, respectively (p = 0.90). Younger patients and patients with a pre-treatment white blood count of less than 30,000/microliters had a significantly longer remission duration and survival. Eleven per cent of patients who achieved a complete remission have had a CNS relapse to date, which is not different from the rate in our prior study using cranial irradiation and i.t. MTX, implying that intermediate dose MTX with i.t. MTX may be as effective as cranial irradiation and i.t. MTX. This study suggests that some form of maintenance chemotherapy is required for the eradication of residual leukemia cells.

Sequential intermediate-dose cytosine arabinoside and mitoxantrone for patients with relapsed and refractory acute myelocytic leukemia.

Based on in vitro evidence of time-dependent synergistic kill of HL-60 leukemia cells exposed to Ara-C and mitoxantrone, 44 patients with relapsed or refractory AML and 3 with blastic CML were treated with a timed sequence of both drugs. There were 25 females and 22 males, with a median age of 53 (range 21-75). Of 31 patients with relapsed AML, 24 had one prior remission, 6 had two and 1 had three. Of these, 15 had failed a second reinduction attempt. Thirteen patients were primarily refractory to induction with Ara-C plus daunorubicin. Each dose of Ara-C, 500 mg/m2, was followed after 6 hr by mitoxantrone, 5 mg/m2, and the sequence was repeated four to six times (44-68 hr) in different cohorts of patients. All but two patients (one with blastic CML and one in relapse and refractory) are evaluable for response and toxicity. Of 16 patients in relapse without prior reinduction 7 achieved CR and 3 PR (62% response rate); there were 3 CR in the 14 patients who were in relapse and refractory (21% response rate) and 4 CR and 1 PR (35% response rate) in the 14 patients with primary anthracycline resistance. Five of seven patients previously exposed to mitoxantrone achieved CR. Response lasted from 2 to 42 months, with two patients alive and in continuing remission at 34 and 42 months. Average marrow recovery was seen after 25 days and time to remission was 30 days. Six patients died in induction (four from sepsis and two from the tumor lysis syndrome) and 21 had progressive disease. Chemotherapy was well tolerated with minor nausea and vomiting in 13 patients, moderate in 20, and severe in 2. Most patients did not have evidence of drug-induced mucositis: it was minor in 9 and moderate in 2. Renal dysfunction was attributable to the use of nephrotoxic antibiotics. Hepatic dysfunction was reversible and was minor in 10 patients, moderate in 13, and severe in 3. Sequential, timed administration of intermediate-dose Ara-C and mitoxantrone is an active and well-tolerated antileukemic regimen.

P185BCR-ABL in two patients with late appearing Philadelphia chromosome-positive acute nonlymphocytic leukemia.

Two patients with acute nonlymphocytic leukemia (ANLL) who had normal karyotypes at diagnosis and developed the Philadelphia (Ph) translocation during leukemia relapse are described in this report. Patient 1 relapsed with Ph-positive acute leukemia, FAB classification M1. The Ig heavy chain locus and T cell receptor gamma and beta genes of relapse cells from this patient were all found to be germline configuration confirming the diagnosis of M1 acute leukemia. Patient 2 displayed a complex karyotypic evolution leading to Ph-positive M4 relapse. Ph-positive relapse specimens from both patients expressed P185BCR-ABL protein and RNA gene products that were identified serologically and by polymerase chain amplification of the BCR-ABL RNA junction. In vitro derived myeloid cell lines from relapse M1 leukemia cells of patient 1 also expressed the P185BCR-ABL protein. In two described patients, late appearance of the Ph translocation that encodes P185BCR-ABL coincided with relapse of acute leukemia. We conclude that P185BCR-ABL may be a strong indicator of Ph-positive acute leukemias.

Human immunodeficiency virus infection in transfused patients with acute leukemia.

The human immunodeficiency virus (HIV) is transmitted by sexual contact and by blood products. Patients with acute leukemia are extensively transfused as part of their supportive care. We conducted a retrospective study of the incidence of HIV antibody positivity in patients treated for acute leukemia at The Mount Sinai Medical Center between 1970 and 1986. Serum samples from 106 patients were studied, including 71 (67%) with at least one posttransfusion specimen. Six were found to have HIV antibodies. All positive specimens occurred in patients treated between 1980 and April 1985, when mandatory HIV testing of blood donors began. Twelve percent of the 51 patients studied from this time period underwent seroconversion documented by the presence of HIV-negative specimens prior to transfusion. These results show that these extensively transfused patients were at significant risk for HIV infection during the time period 1980 to April 1985.

The frequency of long-term remission in patients with acute myelogenous leukaemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years.

Remission duration associated with the administration of conventional maintenance chemotherapy to patients with acute myelogenous leukaemia was evaluated. The records of 760 patients who entered remission between 1974 and 1979 were reviewed. The median duration of remission was 1.1 years with 16% of patients remaining in remission at 8 years. The relapse curve was biphasic with a high rate of relapse during the first 2 1/2 years of remission followed by a much lower relapse rate thereafter. Leukaemic relapses were noted through 8 years of remission. A plateau phase indicating freedom from the risk of leukaemic recurrence is not clearly apparent yet but may exist after the eighth year of remission.

Comparison of erythroid progenitor cell growth in vitro in polycythemia vera and chronic myelogenous leukemia: only polycythemia vera has endogenous colonies.

The ability of erythroid cultures to distinguish among myeloproliferative disorders was examined. We studied 14 patients with polycythemia vera (PV), 11 with chronic myelogenous leukemia (CML), four with non-PV erythrocytosis, two with agnogenic myeloid metaplasia, as well as three normal fetuses and greater than 25 normal adults. Endogenous, i.e. grew without added erythropoietin, bone marrow CFU-E-derived colonies were observed in all but one PV patient. However, endogenous blood BFU-E-derived bursts were observed in only eight of 14 PV patients. Endogenous erythroid colonies were not seen in cultures from any normal adults or fetuses, or patients with CML, erythrocytosis, or myeloid metaplasia. In PV, relative HbF synthesis was always greater in cultures without erythropoietin, while in cultures from all other patients relative HbF synthesis was similar to that observed in cultures from normal individuals. We conclude that PV and CML are distinguishable in culture since CML patients do not have endogenous growth. Most important, endogenous bone marrow CFU-E-derived colonies are the only consistently unique observation in patients with PV, and endogenous CFU-E- and BFU-E-derived colonies and bursts are not uniformly observed in PV blood cultures. In-vitro studies of erythropoiesis to confirm the diagnosis of PV, therefore, require marrow when endogenous colonies and bursts are absent from blood cultures.

Morphologic and cytochemical characterization of adult lymphoid leukemias which express myeloid antigen.

Cancer and Leukemia Group B demonstrated that adults with acute lymphoid leukemia (ALL) possessing blast cells with myeloid antigens (My+ALL), as identified by monoclonal antibodies against CD13 and CD33, have a worse prognosis than those lacking myeloid antigens (My-ALL). Consequently, we further studied this group of adults with ALL to determine if these immunological groups could be distinguished by morphological and cytochemical criteria. Bone marrow films were classified according to French-American-British Co-operative Group Criteria, assessed for myelodysplasia, and examined for blasts with azurophilic granules. More cases of My+ALL had L2 morphology than did My-ALL (68% vs. 49%, p = 0.04), and more cases of My+ALL were positive for acid alpha-naphthyl acetate esterase (61% vs. 31%, p = 0.03). The presence of myelodysplastic changes was not significantly different in My+ALL (13%) as compared to My-ALL (5%), but more cases of My+ALL had unusual blasts (monocytoid features and cytoplasmic buds) than did My-ALL (19% vs. 0%, p less than 0.01). In addition, more cases of My+ALL had greater than 5% of the blasts with azurophilic granules (42% vs. 13%, p = 0.01). In the My+ALL group the presence of azurophilic granules was associated with a longer median survival (13.5 months vs. 1.5 months, p less than 0.01). We conclude that My+ALL can be suspected when cases possess L2 morphology, unusual blasts, positive staining for acid alpha-naphthyl acetate esterase, and greater than 5% azurophilic granules. In addition, the poor risk group (My+ALL) can be further subdivided into better and poorer risk subgroups based on the presence of azurophilic granules.

Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study.

One hundred ninety-five adult patients with refractory or first relapse acute myelogenous leukemia (AML) were randomly assigned to receive high-dose cytarabine (HiDAC), 3 g/m2 as a three-hour intravenous (IV) infusion every 12 hours for four doses, followed by 6,000 IU/m2 asparaginase (ASNase) administered at hour 42, or HiDAC without ASNase. Treatment was repeated on day 8. The median patient age was 52 years. There was an overall superior complete remission (CR) rate for HiDAC/ASNase (40%) v HiDAC (24%), P = .02. Subset analysis according to prior response and age showed the following CR rates: 54% from HiDAC/ASNase treatment of refractory AML in patients less than 60 years, and 31% in patients greater than 60 years; CR from HiDAC in the same refractory groups were 18% (less than 60) and 0% (greater than 60); 37% from HiDAC/ASNase treatment of relapsed AML in patients less than 60 years, and 43% in patients greater than 60 years; CRs from HiDAC in the same relapsed groups were 33% (less than 60) and 21% (greater than 60). Toxicity in the two treatment arms was comparable and consisted primarily of leukopenia, thrombocytopenia, mild hepatic dysfunction, diarrhea, conjunctivitis and serositis, and hyperglycemia. There was only one case of transient cerebellar toxicity and no cutaneous toxicity. Median time to full hematologic recovery was 5 weeks. There was an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks) compared with HiDAC (15.9 weeks), P = .046, primarily attributable to effects in refractory patients. Median time to failure for refractory patients who achieved CR was 38.5 weeks with HiDAC/ASNase, and 13.3 weeks for those treated with HiDAC. For relapsed patients in CR from HiDAC/ASNase the median time to failure was 17.7 weeks and 18.3 weeks for HiDAC. The overall 42% CR rate from HiDAC/ASNase v 12% from HiDAC in patients with refractory AML indicates that HiDAC/ASNase is not cross-resistant with standard-dose cytarabine (SDAC) and anthracyclines. We conclude that HiDAC/ASNase has substantial activity in poor-prognosis AML and that this combination warrants further trials in earlier stage disease.

Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia.

A combination of mitoxantrone, vincristine, and prednisone was used to treat 19 patients with acute lymphocytic leukemia. Of these, 12 were patients with acute lymphoblastic leukemia (ALL) (9 in first relapse and 5 primarily refractory to standard induction therapy with daunorubicin, vincristine, and prednisone), 2 had a phenotypic ALL relapse after an initial diagnosis of acute myelocytic leukemia and 5 had terminal deoxynucleotidyl transferase positive blastic phase chronic myelogenous leukemia (BCML). Eight patients with ALL (and of these, four with primarily anthracycline resistant disease), and two with BCML achieved complete remission. Five patients died in induction (three ALL from sepsis and two BCML from bleeding), and five had progressive disease. Median duration of response was 5 months, with two primarily refractory ALL patients remaining in continuing complete remission at 28 and 31 months. Treatment was well tolerated, with minimal nausea and vomiting, and oral mucositis. Posttreatment transient hepatic dysfunction was seen in 80% of patients. Mitoxantrone, vincristine, and prednisone are an active combination for the treatment of relapsed or refractory ALL and of terminal deoxynucleotidyl transferase positive BCML. The finding that four of five primarily refractory ALL patients were induced in complete remission supports the contention that mitoxantrone and anthracyclines are not cross-resistant.

Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia.

Mitoxantrone is a synthetic aminoanthraquinone we have previously reported to be effective for patients with acute leukemia in relapse. We presently report the results of a trial of mitoxantrone in combination with cytosine arabinoside (ara-C) in patients with refractory or relapsed acute myelocytic leukemia (AML). Forty-nine patients, 24 males and 25 females, with a median age of 56, of whom 32 were in first relapse, four were in second relapse, and 13 had primarily refractory AML, were treated with mitoxantrone 10 mg/m2 daily for 3 days and ara-C 100 mg/m2 daily by continuous infusion for 7 days. Twenty patients (62.5%) with first relapse AML achieved M1 marrow, whereas only two of 13 patients with refractory AML did; none of four patients with more than one prior remission responded. Marrow recovery was observed in a median of 32 days. Remissions were maintained with monthly ara-C plus mitoxantrone alternating with ara-C plus 6-TG; median duration of remission was 8 months and two patients are in continuing remission at 8 and 16 months. Treatment was well tolerated, with minimal nausea and vomiting, diarrhea, drug-induced mucositis. Treatment-related cardiac toxicity was not observed. Transient hepatic dysfunction was observed in greater than 50% of courses. Mitoxantrone plus ara-C is an active combination with great promise for the therapy of previously untreated patients with AML.

High frequency of clonal immunoglobulin or T cell receptor gene rearrangements in acute myelogenous leukemia expressing terminal deoxyribonucleotidyltransferase.

Ig and T cell receptor rearrangements have been used as irreversible markers of lineage and clonality in the study of B- and T-lymphoid populations. We have addressed the issue of lymphoid lineage specificity of these rearrangements by analyzing a panel of 25 TdT- acute myelogenous leukemias, 13 TdT+ AMLs, and 4 TdT+ undifferentiated leukemias. We report that while gene rearrangements represent extremely rare events in classical TdT- AML (less than 8%), rearrangements of either the Ig or T beta locus or both were detectable in the majority of the TdT+ AMLs (greater than 60%), and rearrangements of both loci were detectable in all of the TdT+ undifferentiated leukemias. These data demonstrate a significant association between TdT expression and Ig or T beta gene rearrangements even outside the lymphoid lineage, further supporting a role for TdT in Ig and T cell receptor gene assembly. These data also indicate that a coordinated program of lymphoid gene expression involving TdT-CD7-expression and Ig/T beta rearrangements can be activated before myeloid commitment. Whether the activation of this program represents a normal, albeit rare, event in early myelopoiesis or a transformation-related event present only in leukemic cells remains to be determined.