Zalmen Arlin

High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia

In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

A Cause-Specific Hazard Rate Analysis of Prognostic Factors Among 199 Adults With Acute Lymphoblastic Leukemia The Memorial Hospital Experience Since 1969

Results of a multivariable analysis of prognostic factors are reported for 199 previously untreated adults with acute lymphoblastic leukemia (ALL). These patients have long-term follow-up, and the probability of cure is estimated at approximately 35%. The cause-specific hazard rate analysis found lower rates of achieving complete remission (CR) in patients with WBC greater than 10,000/microL, AUL (undifferentiated) morphology, and older age. Since these patients required additional time to respond, fewer of them actually achieved CR. Characteristics directly associated with a higher rate of death during induction therapy due to severe bone marrow suppression were low serum albumin concentration (less than or equal to 3.5 g/dL), age greater than 50 years, acute undifferentiated leukemia (AUL) morphology, low Karnofsky performance status, and weight loss greater than 5%. Factors associated with a higher rate of relapse were WBC greater than 20,000/microL, non-T cell ALL, age greater than 60 years, Ph + ALL, and time to achieve CR greater than 5 weeks. These criteria were used to identify patients at high risk of relapse. In addition, the predictive value of high WBC was found to disappear by 18 months of continuous CR. Finally, the rate of death following first relapse was higher in patients with a short first remission duration, high percentage weight loss at initial diagnosis, and older age. In summary, factors associated with a higher rate of death during attempted induction (ie, low albumin, high percent weight loss, and poor performance status) had no association with the patients ability to remain relapse-free. Conversely, factors correlating with more extensive or resistant disease (ie, high WBC, null or B cell ALL, or Ph + ALL) showed no association with the ability to tolerate therapy. Thus, a less toxic but more effective induction regimen is needed for patients with a poor clinical status, whereas a more intensive form of therapy appears warranted for patients presenting with more extensive or resistant disease.

Treatment of acute lymphoblastic leukemia in adults: results of the L-10 and L-10M protocols.

Two successive protocols (L-10 and L-10M) employing multidrug induction therapy with vincristine, prednisone, and doxorubicin (Adriamycin) plus an intensive consolidation phase and maintenance program have led to a significant improvement in the prognosis of adult acute lymphoblastic leukemia (ALL). The complete remission (CR) rates for the 34 patients entered on the L-10 protocol and the 38 patients entered on the L-10M protocol were 85% and 84%, respectively. The median duration of remission has not yet been reached for either the L-10 (median follow-up, 5.5 years; range, 3.5-7.5 years) or the L-10M protocol (median follow-up, 2.5 years; range, 1-3.5 years). The median survival time has not yet been reached for the L-10M protocol. Central nervous system prophylaxis with intrathecal methotrexate alone was effective in preventing central nervous system relapse. An analysis of possible prognostic factors indicated that patients less than 25 years of age had a higher CR rate than older patients (p = 0.02). Patients with an initial leukocyte count below 15,000/microL experienced longer remissions than patients with a leukocyte count above 15,000/microL (p = 0.008), and patients who achieved CR within the first month of therapy were in remission longer than those requiring a longer time to achieve CR (p = 0.04). Patients with T cell ALL did not have a poorer prognosis than other patients treated on these protocols. The L-10 and L-10M protocols were well tolerated with minimal morbidity.

Lymphoblastic lymphoma in adults.

Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.

A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia.

Using a loading dose/continuous infusion schedule, fludarabine phosphate was administered to 51 patients with previously treated chronic lymphocytic leukemia (CLL). All patients had evidence of active disease, and the majority had advanced Rai stages. Of the 42 patients assessable for response, 22 (52%) achieved a partial response, five (12%) had stable disease, and 15 (36%) progressed. Thirteen of the 22 responders improved their Rai stages with fludarabine therapy, including six patients who achieved stage 0. Response rates for pretreatment stages III and IV were 60% and 53%, respectively. Patients with final Rai stages 0 to II had better survival than those with stages III and IV. Patients who had undergone splenectomy before starting therapy were more likely to respond. Myelosuppression was the primary toxicity and did not appear to be cumulative. Severe leukopenia and thrombocytopenia, although infrequent, were associated with several deaths in the early cycles of treatment. Nonhematologic toxicity was mild with no serious neurotoxicity noted. Infections were common with 22 minor, 18 major, and 10 fatal episodes. Fludarabine phosphate by this alternative dosing schedule is effective in refractory advanced CLL and is well tolerated by the majority of patients.

The acute monocytic leukemias: Multidisciplinary studies in 45 patients

The clinical and laboratory features of 37 patients with variants of acute monocytic leukemia are described. Three of these 37 patients who had extensive extramedullary leukemic tissue infiltration are examples of true histiocytic lymphomas. Three additional patients with undifferentiated leukemias, one patient with refractory anemia with excess of blasts, one patient with chronic myelomonocytic leukemia, one patient with B-lymphocyte diffuse histiocytic lymphoma and one patient with null cell, terminal deoxynucleotidyl transferase-positive lymphoblastic lymphoma had bone marrow cells with monocytic features. Another patient had dual populations of lymphoid and monocytoid leukemic cells. The true monocytic leukemias, acute monocytic leukemia (AMOL) and acute myelomonocytic leukemia (AMMOL), are closely related to acute myelocytic leukemia (AML) morphologically and by their response to chemotherapy. like AML, the leukemic cells from the AMMOL and AMOL patients form leukemic clusters in semisolid media. Cytochemical staining of leukemic cells for nonspecific esterases, presence of Fc receptor on the cell surface, phagocytic ability, low TdT activity, presence of surface ruffles and ridges on scanning EM, elevations of serum lysozyme, and clinical manifestations of leukemic tissue infiltration are features which accompanied monocytic differentiation in these cases.

Treatment of advanced hodgkin's disease with chemotherapy and irradiation: Controlled trial of two versus three alternating, potentially non-cross-resistant drug combinations

From January 1979 to June 1983, 71 evaluable, previously untreated patients with advanced Hodgkins disease completed a randomized trial of two or three potentially non-cross-resistant drug combinations and low-dose radiotherapy to initially involved nodal regions (2,000 to 3,000 rads). All patients received nine cycles of alternating chemotherapy regimens and radiotherapy between cycles 6 and 7. Thirty-four patients received three combinations: lomustine, melphalan, vindesine (CAD), MOPP, and doxorubicin, bleomycin, vinblastine (ABV). The complete remission rate was 82 percent, partial remission rate 12 percent, and progression rate 6 percent. There were two relapses from complete remission and three deaths. Thirty-seven patients received MOPP and ABV plus dacarbazine (D). The complete remission rate was 78 percent, partial remission rate 16 percent, and progression rate 6 percent, with three relapses from complete remission and five deaths. Myelosuppression was more frequent with CAD/MOPP/ABV/radiotherapy, and nausea and vomiting with MOPP/ABVD/radiotherapy. The results for both are among the best reported, and CAD/MOPP/ABV/radiotherapy was more acceptable to patients.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia.

Six men with acute lymphocytic leukemia (ALL) were studied prospectively to assess the effect of treatment with the L‐10 protocol on reproductive capacity. Before therapy three men had fathered children (two, two children; one, three children); the others were sexually mature although no fertility studies had been done prior to or during their treatment. Each patient had a minimum of 31/2 years of continuous chemotherapy as part of this study. Semen analysis was done 10 to 52 months (median, 31.5 months) after completion of therapy. One patient had lower than normal sperm concentration but near normal total sperm count and normal motility; the others had a normal sperm concentration and motility. Sperm nuclei were isolated from each sample and analyzed by flow cytometry for resistance to DNA denaturation in situ; all samples had relatively high resistance to denaturation, consistent with a normal, fertile reproductive status. After completion of therapy, one patient fathered a normal child, and a second patient fathered one child with multiple congenital malformations followed by a second child who was normal. Cancer 53:30‐36, 1984.

Prognostic significance of terminal deoxynucleotidyl transferase activity in acute nonlymphoblastic leukemia.

Bone marrow and/or peripheral blood samples from 133 (75%) of a total of 177 consecutive previously untreated protocol patients with acute nonlymphoblastic leukemia (ANLL) were analyzed for terminal deoxynucleotidyl transferase (TdT) activity at the time of presentation. Twenty-nine (22%) were found to exhibit TdT activity (greater than or equal to 0.10 U/10(8) cells, TdT+) as measured in a biochemical microassay. There were no differences between TdT+ as compared with TdT-negative (TdT-) patients with respect to age, sex, French-American-British (FAB) classification, or the presence of Auers rods. Remission induction rates were higher for the TdT- patients, with 68% v 48% for the TdT+ patients (P = .05). TdT- patients also experienced longer remissions (P = .003) than TdT+ patients, especially in the Auers rod-positive subgroup (P = .002). None of five patients with TdT+ ANLL treated with vincristine and prednisone as initial therapy achieved complete remission; all required induction regimens containing daunorubicin or amsacrine in combination with cytosine arabinoside and 6-thioguanine. It is concluded that TdT activity in ANLL indicates biphenotypia or lineage infidelity and is associated with a poor prognosis on chemotherapy protocols currently used for the treatment of ANLL.