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BACKGROUND: Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours. METHODS: A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged

Novel agents have demonstrated enhanced efficacy when combined with other antimyeloma agents especially dexamethasone. The steroid doses employed in myeloma regimens are often poorly tolerated. Therefore, in a phase II clinical trial we investigated the efficacy of a steroid-free combination including bortezomib, pegylated liposomal doxorubicin and thalidomide (VDT regimen). Twenty-three patients with relapsed or refractory myeloma or other plasma cell cancers were treated with the VDT regimen. Patient had a median of five prior therapies and 65.2% were refractory to their last regimen. The overall response rates were 55.5% and 22%, respectively. The median progression free survival was 10.9 months (95% CI: 7.3-15.8) and the median overall survival was 15.7 months (95% CI: 9.1-not reached). Fatigue and sensory neuropathy were the most common side effects noted. We observe that VDT is an effective steroid-free regimen with ability to induce durable remission even in patients with refractory myeloma.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) have been reported only rarely following treatment of AML. We report five patients treated for de novo AML who developed t-MDS/t-AML, all with chromosome 7 abnormalities, including -7, del(7)(q22q36) and del(7)(p11.22p22). All had been treated with cytarabine, topoisomerase 2 inhibitors and granulocyte or granulocyte-monocyte colony-stimulating factor and three with alkylating agents as part of autologous transplant regimens. These cases further document t-MDS/t-AML as a complication of therapy for AML. Presence of chromosome 7 abnormalities in patients with and without prior alkylating agent therapy suggests possible association with the antimetabolite cytarabine.

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing-remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities.

Dasatinib (DA, Sprycel,® Bristol-Myers Squibb) is an oral tyrosine kinase inhibitor indicated for treatment of patients with chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) ...

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m(2)/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m(2)), doxorubicin 35 mg/m(2)/day as a continuous infusion on Days 1 and 2 (total 70 mg/m(2)), vincristine 1.4 mg/m(2) (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible.

A growing body of literature reports therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) in patients treated successfully for acute promyelocytic leukemia (APL). We report a t-MDS with an isochromosome 1q as a sole abnormality, 47,XY,+1,i(1)(q10), in a 46-year-old man with APL 14 years after he was treated with cytosine arabinosine and daunorubicin. The literature on t-MDS/t-AML after APL therapy and on isochromosome 1q is reviewed.

Purpose HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients. Methods This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology. Results Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (κ = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy. Conclusion FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.

This paper reports a 73-year old woman with simultaneous presentation of acute monoblastic leukemia (acute myeloid leukemia (AML), French-American-British (FAB) type M5a) and mantle cell lymphoma. The patient presented with wasting, generalized lymphadenopathy, an extensive infiltrative rash and pancytopenia. Bone marrow and lymph node histopatholology showed extensive infiltration by leukemic monoblasts. Marrow cytogenetics revealed a complex karyotype, including t(8;16)(p11;p13). Flow cytometric immunophenotyping of peripheral blood, lymph node and bone marrow demonstrated two populations, expressing CD5, CD19, CD20 and CD22 and CD45, HLA-DR, CD13, CD33, CD14 and CD38, respectively. A focus of abnormal lymphocytes in the lymph node biopsy demonstrated BCL1 expression and t(11;14)(p11;p13) by fluorescence in situ hybridization and immunoglobulin heavy chain gene rearrangement by the polymerase chain reaction. The patient received infusional cytarabine, daunorubicin and etoposide chemotherapy, with complete remission of both the AML and the mantle cell leukemia. To the authors' knowledge, this is the first report of simultaneous presentations of AML, FAB M5a and mantle cell lymphoma. The case is discussed and the literature is reviewed.

Massive hyperdiploidy (>50 chromosomes) and tetraploidy (4n) are rare cytogenetic abnormalities in myelocytic malignancies, and their significance is unknown. We report on 11 patients with acute myelocytic leukemia (AML) and two patients with a myelodysplastic syndrome (MDS) with massive hyperdiploidy (10 patients) or tetraploidy (3 patients) seen at our institution over a 12-year period. Eleven patients were male and two were female. Age range was 44–84 years (median, 70 years). Only one AML patient had a previous MDS, and no patient had therapy-related disease. One or more copies of chromosomes 8 and 19 were gained in eight patients each; other frequently gained chromosomes included 13, 15, and 21. Eight patients had structural abnormalities in addition to chromosome gain; del(5q) was most common (five patients). Eleven patients received induction chemotherapy, but only four achieved complete remission. Survival ranged from 1 to 22 months, with a median of 6 months. We conclude that massive hyperdiploidy and tetraploidy are infrequent abnormalities in AML and MDS, are seen primarily in de novo disease in older male patients and are associated with a low remission rate and short survival. Massive hyperdiploidy and tetraploidy define a prognostically unfavorable cytogenetic group in de novo AML.

BACKGROUND The objective of the current study was to evaluate the efficacy of intensive chemotherapy with and without cranial radiation for central nervous system (CNS) prophylaxis in adults with Burkitt leukemia or lymphoma. METHODS Patients received 18 weeks of therapy. Prophylactic cranial radiation (2400 centigrays) and 12 doses of triple intrathecal chemotherapy were administered to the first cohort of patients. A subsequent cohort received the same therapy, with the exceptions that intrathecal therapy was reduced to six doses and radiotherapy was administered only to high-risk individuals. RESULTS The median follow-up durations were 6.8 years in Cohort 1 and 4.1 years in Cohort 2. Three occurrences of transverse myelitis, 2 severe neuropathies, 3 cases of aphasia, and 1 case of blindness were documented in the first cohort of 52 patients (Cohort 1). In the subsequent cohort of 40 patients (Cohort 2), none of these occurrences were observed, and patients experienced less neurologic toxicity overall (61% vs. 26%; P = 0.001). Responses were similar, and the 3-year event-free survival rate was 0.52 (95% confidence interval, 0.38–0.65) for Cohort 1 and 0.45 (0.29–0.60) for Cohort 2. CONCLUSIONS Intensive, short-duration chemotherapy with less intensive CNS prophylaxis led to control at this sanctuary site with little neurotoxicity and may be curative for adults with Burkitt leukemia or lymphoma. Cancer 2004;100:1438–48. ©2004 by the American Cancer Society.

Human leukocyte antigen (HLA) Class II antigens are variably expressed on acute myeloid leukemia (AML) blasts. The biological and clinical significance of HLA Class II antigen expression by AML cells is not known. Therefore, we sought to characterize cases of AML without detectable HLA-DR expression. Samples from 248 consecutive adult AML patients were immunophenotyped by multiparameter flow cytometry at diagnosis. HLA-DR antigens were not detected on AML cells from 43 patients, including 20 with acute promyelocytic leukemia (APL), and 23 with other subtypes of AML. All APL cases had t(15;17), but there were no characteristic chromosome abnormalities in non-APL cases. No direct expression of other antigens was identified in HLA-DR-negative APL and non-APL cases. Interestingly, cells from three HLA-DR-negative non-APL patients had similar morphology to that of the hypogranular variant of APL. This morphology, however, was not present in any HLA-DR-positive AML cases. Treatment response was similar in the 23 HLA-DR-negative non-APL and the 205 HLA-DR-positive patients. Finally, relapse was infrequently associated with changes in HLA-DR antigen expression, as the HLA-DR antigen was lost at relapse in only 4% of HLA-DR-positive cases, and was gained at relapse in only 17% of HLA-DR-negative cases. We conclude that HLA-DR-negative AML includes approximately equal numbers of APL and non-APL cases, and that the morphology of HLA-DR-negative non-APL cases can mimic the hypogranular variant of APL. The diagnosis of APL cannot be based on morphology and lack of HLA-DR antigen expression; rather, it requires cytogenetic or molecular confirmation.

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14–21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38°C) or bacteriologically documented infection in ≥50% of the cycles, or (2) grade ≥2 hemorrhage in association with thrombocytopenia of grade ≥3 severity occurred in ≥50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of grade ≥3 occurred in ≥50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial ...

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14-21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38 degrees C) or bacteriologically documented infection in50% of the cycles, or (2) gradeor = 2 hemorrhage in association with thrombocytopenia of gradeor = 3 severity occurred in50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of gradeor = 3 occurred in50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial response rates, and the time to treatment failure (TTF). The trial also attempted to assess the effectiveness of this treatment program in eradicating Bcl-2 rearrangements by PCR, and to assess complete remission duration in relationship to PCR results in patients who respond to this chemotherapy program. Patients were required to have histologically documented non-Hodgkin's lymphoma of the subtypes follicular, predominantly small cleaved cell (IWF-B) or follicular mixed, (IWF-C). Patients were required to have Stage IV disease including histologic evidence of bone marrow involvement. Measurable disease was required and patients were also required to have one of the following risk factors:or = 2 extranodal sites, node or nodal groupor = 5 cm. Submission of fresh bone marrow for molecular genetic studies for the presence of Bcl-2-Ig fusion DNA was mandatory in previously untreated patients. Patients had to be between 18 and physiologic age 55 years (carefully selected patients over age 55 years were also eligible), expected survival2 years, performance status 0-1, and have adequate renal, hepatic and bone marrow function, and a cardiac ejection fractionor = 50%. Cyclophosphamide 4.5 g/m2 i.v. was given with mesna every 14 days with rhG-CSF support. Twenty-nine patients were accrued to this trial. The median follow-up time is 5.0 years, with a range of 2.5-6.7 years. The overall response rate was 75% (9 CRs 37.5%, 9PRs 37.5%). The median duration of survival is 5.53 years. The 1-year estimated probability of freedom from treatment failure was 50% and of survival at 1 year was 92%. No strong association was observed between TTF and age, symptomatic stage, histology performance status, number of extranodal sites or baseline Bcl-2 status. At 3 years the survival of all patients was 78% and failure free survival was 17%. 15 (62%) of the 24 eligible previously untreated patients met the criteria for feasibility specified in the protocol. The 95% CI for the feasibility rate is (44 and 82%). Twenty-two of the 24 (92%) previously untreated patients had specimens submitted for testing for Bcl-2 rearrangements. Thirteen of the 22 (59%) were found to have rearrangements at baseline. Post-treatment specimens were submitted for seven of the 13 patients. Four of the seven converted to Bcl-2 negative following treatment. Eight of 13 Bcl-2 positive patients (62%) had a clinical response to treatment. The 95% exact binomial CI for the total response rate in this subgroup is (28 and 88%). This study demonstrates that repetitive doses of cyclophosphamide at 4.5 g/m2 every two weeks with rhG-CSF support can be administered to selected younger patients with advanced follicular lymphoma with morphologic involvement of the bone marrow with acceptable non-hematologic toxicity.

Summary Background Patients with resistant diffuse aggressive non-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggested infusional therapy may be beneficial. Patients and methods This trial used an infusional regimen called I-CHOPE in resistant patients who had previously received only bolus CHOPE or CHOP regimen. Resistance was defined as: a) primary refractory disease, b) progression on therapy, c) partial response, d) complete remission lasting less than one year. Eligibility criteria included a diagnosis of DA-NHL (IWF E-H), no prior irradiation and adequate organ function. Results Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology (5) and other (3). The median age was 57 years (range 29–81) with 21 males. The performance status scores were: 0 (12 patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2day. Cyclophospharnide 750 mg/m2 was given as an iv bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1–5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR 31%). Freedom from progression was 24% at six months and 8% at one year. Survival was 69% at six months and 40% at one year. In an exploratory analysis a prior CR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had a CR/PR on previous therapy responded while two of thirteen who had no prior response, responded to I-CHOPE (P = 0.003). The toxicity was tolerable with grade 3–4 hematologic toxicity being leucopenia 94% and thrombocytopenia 41%. The grade 3–4 non-hematologic toxicities were infection in 28%, phlebitis in 11%, and stomatitis in 15%. Conclusions I-CHOPE can induce responses in this group of patients with a poor prognosis, but most were seen in those who had previously had a response to bolus chemotherapy.

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Two monoclonal antibodies (MoAbs) B121 and B124 to the human lymphocyte differentiation antigen E5′-NT (CD73), and the MoAbs 27.2 and 27.1 that were raised to HTLV-1+CD4+CD25+ leukemic T cells were tested immunohistochemically on frozen sections of 13 cases of MF together with Leu13, CD28, LAM-1(Leu8) and other standard T-cell markers. Controls included 7(5T, 2B) non-MF cutaneous non-Hodgkin's lymphomas (NHL), 2 cutaneous T lymphoid leukemias (T-ALL), 13 miscellaneous non-neoplastic dermatoses, 11(5T, 6B) extracutaneous NHL, and 5 splenic B-hairy cell leukemias. Previous studies suggest that 27.2 also recognizes the CD73 antigen and is present in high density in some cases of HTLV-1+ adult thymic leukemia/lymphoma (ATL) and HTLV-1- Sezary syndrome (Y. Fukunaga et al., Blood 74:2486-2492, 1989). In the studies reported here B121, B124 and 27.2 reacted similarly with the MF and control samples tested. The CD73 antigen was present in the majority of lymphoid cells from 8 (62%) of 13 cases of MF. In one of th...

Bromodeoxyuridine (BrdU) was administered to 128 newly diagnosed patients with standard risk acute myelocytic leukaemia (AML) for cell cycle measurements. Labelling indices (LI) were obtained from both the bone marrow aspirate (BMasp) and biopsies (bx) and durations of S-phase (Ts) and total cell cycle time (Tc) were measured by double-labelling the S-phase cells in vitro with tritiated thymidine. Median LI BMasp was 8% and from BMbx was 25%. The median Ts was 12 h (range 3.1-35 h) and Tc was 48 h (range 11.5-211 h). All patients received induction therapy with a combination of cytosine arabinoside and an anthracycline. Outcome of therapy or FAB type were not related to cell cycle characteristics. Patients with above median LI BMasp, however, had longer remission durations (P = 0.03) as did patients with above median Ts (P = 0.03) and Tc (P = 0.03). Upon longer follow-ups, even some of the patients with slowly cycling myeloblasts have relapsed (log rank P = 0.453 and 0.203 for Ts and Tc respectively). We conclude that patients with rapidly cycling cells tend to relapse faster; however, slowly cycling nature of myeloblasts is not associated with curability.

To further evaluate possible non-cross-resistant regimens in Hodgkin's disease, a phase II trial utilizing antimetabolites and etoposide was initiated by the Cancer and Leukemia Group B (CALGB). Etoposide was included because of its known efficacy in relapsed Hodgkin's disease and to evaluate for synergy with an alkylating agent and vincristine. Cytosine arabinoside and methotrexate were included to evaluate their effectiveness in rapidly growing resistant disease. Forty-two patients with previously treated Hodgkin's disease were entered, of which 37 are evaluable for response and toxicity. All patients had at least 2 prior regimens of chemotherapy and 59% had additional radiation therapy. Complete and partial response was observed in 61%; there were 32% complete responders. Duration of complete response was a median of 8 months (range 2-28+ months). Duration of partial response was 7 months (range 1-17 months). Three patients remain in complete remission at 19, 19, and 28 months. Major toxicity was hematologic with severe or life-threatening toxicity in 54%. There was one patient with a fatal infection. Non-hematologic toxicity, save for nausea and vomiting, was mild and uncommon. There were two fatal and one severe pulmonary toxicities reported in patients who had previous exposure to bleomycin and mediastinal radiation. Three had interstitial pneumonitis and one pulmonary emboli. The interstitial pneumonitis was thought to be drug related. Survival of the entire group is estimated at 61% at 12 months. We conclude that MOPLACE is an effective regimen with an appreciable complete response rate in this heavily pretreated group of patients. Hematologic and pulmonary toxicities are severe and may necessitate dose modifications. The use of etoposide containing combinations requires further study as primary therapy in untreated patients.

We describe 15 patients (9 children) with precursor B-cell (pB) acute lymphoblastic leukemia (ALL) with surface immunoglobulin (sIg) light chain restriction revealed by flow cytometric immunophenotyping (FCI). The same sIg+ immunophenotype was present at diagnosis and in 3 relapses in 1 patient. In 15 patients, blasts were CD19+ CD10+ (bright coexpression) in 14, CD34+ in 12, surface kappa+ in 12, surface lambda+ in 3; in 8 of 8, terminal deoxyribonucleotidyl transferase (TdT)+; and in 4, surface IgD+ in 2 and surface IgM+ in 1. The 3 CD34- cases included 1 TdT+ case, 1 with t(1;19)(q23;p13), and 1 infant with 70% marrow blasts. One adult had CD10- CD19+ CD20- CD22+ CD34+ TdT+ sIg+ blasts with t(2;11)(p21;q23). Blasts were L1 or L2 in all cases (French-American-British classification). Karyotypic analysis in 12 of 12 analyzable cases was negative for 8q24 (myc) translocation. Karyotypic abnormalities, confirmed by fluorescence in situ hybridization in 6 cases, included hyperdiploidy, t(1;19)(q23;p13), t(12;21)(p13;q22), t(9;22)(q34;q11), t(2;11)(p21;q23), and trisomy 12. The sIg light chain restriction in pB ALL might be present in neoplasms arising from the early, intermediate, and late stages of precursor B-cell maturation; sIg light chain restriction revealed by FCI does not necessarily indicate a mature B-cell phenotype, further emphasizing the importance of a multidisciplinary approach to diagnosing B-lymphoid neoplasms.

Detection of extra-medullary relapse of acute lymphoblastic leukemia by radiographic imaging following allogeneic hematopoietic SCT

The aberrant expression of antigens (Ag) in lymphoproliferative disorders may cause a diagnostic problem when single parameter immunohistochemical assays are performed on frozen or paraffin sections because coexpression by relevant cells is not determined. This aberrant expression also raises the question as to whether mixed lineage (biphenotypic) lymphoid proliferations exist. Marrow (6) and extramedullary (20) tissues from 26 patients with diffuse, intermediate and high grade, B-cell lymphomas (IWF E=1, F=1, G=19, H=1 and J=4) were analyzed with 19 markers using 3-color flow cytometry. The percentages (%) of patients with double Ag coexpression in at least 20% of the CD19+ or CD20+ lymphoma cells were: stem cell (SC) Ag: CD10 = 58 and CD34 = 15; T-cell Ag: CD2 = 38, CD5 = 19 and CD7 = 19; myeloid (My) Ag: CD13 = 19 and CD33 = 8. The corresponding % with unusual triple Ag coexpression in at least 10% of the CD19+ B-cells were SC+T+ Ag: CD10CD2 = 50, CD10CD5 = 27, CD10CD7 = 38, CD34CD2 = 31, CD34CD5 = 19 and CD34CD7 = 27; T+T+ Ag: CD2CD5 = 35, CD2CD7 = 42 and CD5CD7 = 31; T+My+ Ag: CD2CD13 = 35 and CD2CD33 = 12; and My+My+ Ag: CD13CD33 = 12. Ten of 12 lymphomas tested showed clonal immunoglobulin (Ig) heavy chain gene rearrangements in the absence of clonal T-cell receptor (TCR) gene rearrangements. None (0%) of the My Ag positive cases showed immunoreactivity for myeloperoxidase. We conclude that the anomalous T and My Ag expression seen in the above B-cell lymphomas is not indicative of mixed lineage proliferation but represents the aberrant expression of these antigens by the malignant cells.

A case of a 10-year-old boy with American Burkitt lymphoma is presented in whom a 14q+ due to t(8;14)(q23;q32) was shown to exist in the ascitic lymphoma cells. This appears to be the first demonstration of such a translocation in uncultured material. In addition, another translocation involving the X chromosome, hitherto not observed in Burkitt tumors, was demonstrated. The karyotypic findings have been related to the cytogenetic experience in Burkitt and other lymphomas, with emphasis being put on the importance of the 14q+ anomaly in lymphoproliferative diseases.

Malignant histiocytosis (MH) is a rapidly fatal systemic disease for which there is no adequate therapy. A case of MH with involvement of both eyes resulting in bilateral blindness is presented. Infiltration with malignant cells was seen in the ciliary bodies at autopsy. Attempts at treatment for this complication are discussed.

Bone marrow biopsies were prospectively performed on 75 patients with chronic lymphocytic leukemia (CLL). There was a highly significant relationship (p less than 0.002) between clinical stages and bone marrow infiltration patterns. Ten (50%) of 20 patients with diffuse patterns died; the estimated median survival time for these patients was 87 months. In contrast, only six (11%) of 55 patients with nondiffuse patterns died; the estimated median survival time for these patients could not be computed. When both clinical stage and infiltration pattern were evaluated for survival, a highly significant association between clinical stage and survival time was still observed (p less than 0.003) whereas bone marrow infiltration pattern was no longer significant. A significant association was also observed between bone marrow infiltration patterns and absolute lymphocyte counts (p less than 0.0005), Fc-receptor-positive cells (p less than 0.002), 3H-thymidine uptake of leukocytes (p less than 0.01), serum alkaline phosphatase levels (p less than 0.05), monoclonal urinary-free light chain status (p less than 0.05), and cytogenetics of leukemic cells (p less than 0.05). These observations lead to the conclusion that in an overall prognostic evaluation of patients with CLL, although bone marrow histopathology may have no additional value over a well-established clinical staging system, as a whole, it may be of clinically predictive value in disease progression of patients with stage I and II.

A patient with multiple myeloma, IgG kappa type, developed erythroleukemia with cytogenetic abnormalities three years after diagnosis. The latter disease progressed terminally to acute granulocytic leukemia. Anti-idiotype antibody reagents were prepared by injecting rabbits with the purified monoclonal IgG kappa obtained from the patient's serum and subsequent absorption of the antisera with normal IgG coupled to Sepharose 4B. These reagents reacted specifically with autologous myeloma cells but failed to react with all tested allogeneic cells: these included myeloma cells, reactive lymphocytes and plasma cells, and established lymphoid cell lines. Common idiotypic determinants were found in lymphoid and plasmacytic cells of the patient's marrow, spleen, lymph node, and gastrointestinal tract at autopsy that were not present in the leukemic population. The findings indicate that myeloma and granulocytic leukemia cells have separate clonal origins.

Summary The Leukemia Intergroup Study has treated 110 patients with acute nonlymphocytic leukaemia with ‘high dose’ cytosine arabinoside remission induction therapy and studied the factors which were related to the outcome of therapy. With respect to death during remission induction therapy, only patient age was of prognostic significance. Treatment failure due to resistant leukaemia was associated with a high pretherapy leukaemic cell mass, the presence of few cells in S phase, and insensitivity of DNA synthesis to cytosine arabinoside. If, after 6 d of therapy, more than 40% of the marrow cells were leukaemic, the patient almost invariably failed to enter complete remission because of persistent leukaemia. Simultaneous consideration of the pretherapy labelling index and the per cent abnormal cells in the day 6 marrow permitted a distinction to be made between almost all patients who would enter remission or fail therapy because of persistent leukaemia.

Two hundred and fifty-six patients with a wide variety of advanced neoplasms who were treated with adriamycin at Roswell Park Memorial Institute were studied for electrocardiographic changes. All the patients had pre- and posttreatment electrocardiograms (ECG's) and changes were found in 85 (33.2%). In the group of 168 patients with normal pretreatment ECG's, changes occurred in 51 (30.3%). In the group of 88 patients who had abnormal pretreatment ECG's, 34 (38.6%) developed further changes following treatment. Twenty-five patients received cytoxan concomitantly and ECG changes developed in 12 (48%); however, this and the above differences were not statistically significant. Frequency of ECG changes was higher and the extent of histologic abnormality in the myocardium was greater in those patients who received high doses of adriamycin. Arrythmias were rather benign and only a small number of patients required treatment. ECG changes following adriamycin treatment occurred more frequently than previously reported.

The present report describes the first case of well-differentiated nodular lymphocytic lymphoma evolving into Lennert lymphoma of T-cell origin. A 58-year-old white female developed malignant lymphoma, well-differentiated, lymphocytic type, nodular, with focal bone marrow involvement (stage IV) in May 1975. She received 16 cycles of cyclophosphamide and prednisone combination chemotherapy which was completed in October 1976. A complete remission was achieved. In December 1976, she relapsed and was treated with cyclophosphamide, vincristine, bleomycin, and prednisone until May 1977. Lymphadenopathy decreased until August 1978, but then increased again. Biopsy of an axillary lymph node was interpreted as Lennert lymphoma. She received methotrexate, cyclophosphamide, vincristine, adriamycin, and prednisone beginning in September 1978. When last seen in November 1979, she was in partial remission. Lymphoid cells obtained from lymph node which was involved with Lennert lymphoma consisted of 93% standard E-rosettes and 83% gravity E-rosettes. Cytoplasmic immunoglobulin on frozen sections was negative, but acid phosphatase (ACP) and alpha-naphthyl acetate esterase reactions were strongly positive. These findings support a T-cell proliferation in Lennert lymphoma. A review of the literature reveals only four cases of Lennert lymphoma of T-cell origin.