Phase II study of continuous-infusion diaziquone in relapsed/refractory acute nonlymphocytic leukemia

A total of 74 patients with relapsed/refractory acute nonlymphocytic leukemia were entered in a phase II trial of diaziquone (AZQ) administered by continuous infusion at a dose of 28 mg/m2 a day for 5 days. Complete remission (CR) was achieved in 12 of the 67 evaluable patients (18%), all occurring in relapsed patients (12 of 55, 22%). There were eight partial responders (one of whom was in the refractory group). Three of these had normal M-1 bone marrow but did not meet peripheral blood criteria for CR. The median duration of CR was 13.6 weeks (range, 4-40+). Nonhematologic toxicity was mild to moderate and easily manageable. Hematologic toxicity was severe or life threatening in all patients. This study confirms the activity of AZQ when given as a continuous infusion to patients with relapsed acute nonlymphocytic leukemia.     

High doses of ara-C and m-AMSA in the treatment of refractory acute non lymphocytic leukemia

From November, '85 to March, '87, 17 patients (12 males and 5 females, median 28 years) with resistant or relapsed ANLL received HiDAC (3 g/m2 c.i. 3 hs every 12 hs, day 1-4) + m-AMSA (100 mg/m2 i.v. day 5-7) as salvage therapy: 8/17 patients (47.1%) achieved CR, 7/17 (41.1%) were resistant and 2/17 (11.8%) died during induction; 8/10 relapsed patients achieved a 2nd CR, while all 7 primary resistant patients failed to. Median period of PMN less than 0.5 x 10(9)/l was 28 days, median period of PLTS less than 30 x 10(9)/l was 25 days. All patients had infections during aplasia. Median CR duration was 6.6 months, while median survival of responders was 10.6 months. Two patients with severe induction-related complications relapsed after 2 and 5 months, respectively: 1 patient underwent BMT and relapsed after 21 months; 5 patients, 4 of whom had received a prior ABMT during 1st CR, underwent ABMT: 3 died from ABMT related toxicity and 2 relapsed after 8 and 18 months, respectively. We conclude that HiDAC + m-AMSA is highly effective in relapsed, but not in resistant patients with acceptable hematologic and extra-hematologic toxicity. The role and modalities of ABMT in prolonging a 2nd CR are at present controversial.     

Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia

Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m², cytarabine (AraC) 2 g/m², and liposomal daunorubicin 80 mg/m²]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2–18) and 8 months (range: 2–26), respectively. Median survival among these patients was 8 (range: 1–40) and 12 (range: 1–30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.     

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine+idarubicin+etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease.     

Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience

The present study reports the Spanish PETHEMA group experience in 31 heavily pretreated relapsed/refractory acute lymphoblastic leukemia (ALL) and lymphoma (LL) patients treated with clofarabine-based regimens. The complete remission (CR) rate was 31% (median CR duration of 3 months [range 2–28]) and the overall survival probability at 1 year was 10% (95%CI 4–16%). Responses were seen in B and T lineage diseases and in patients with adverse cytogenetics. Hematological and infectious grade >3 toxicities were found in 100 and 67% of the patients, respectively, with 7 (23%) treatment-related deaths. Other organ toxicities were infrequent. Clofarabine-based chemotherapy regimens might induce CRs in ALL and LL patients, but hematological toxicity and infections may limit their use in heavily pretreated patients.     

Clinical effects of low-dose Ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes

Forty-eight patients with acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes (MDS) were treated with low-dose Ara-C regimen (LDAC) (10 mg/m2 or 10 mg/body subcutaneously every 12 hours). Complete remission (CR) was obtained in sixteen patients (33%) and partial remission (PR) in six (16%). Seven of eight patients with hypoplastic leukemia entered CR. However, LDAC was not effective in MDS and ANLL developing from MDS. The rate of CR was 20% in relapsed or refractory ANLL. Relapse was occurred in thirteen patients until now. The median duration of remission was 7 months (range: 3-20 months). Seven of the sixteen patients who achieved CR were received LDAC at the same dose for 10 days every month as a maintenance therapy. The duration of CR of these patients was shown to be longer than that of the patients without any maintenance therapy. Myelosuppression was observed in nearly all of them and the other clinical findings including cytogenetic analysis indicated cytotoxicity rather than differentiation as the mechanism of LDAC. LDAC was effective especially in hypoplastic leukemia and the maintenance therapy was found to prolong the duration of CR.     

Treatment of relapsed and refractory acute myeloid leukemia with diaziquone and mitoxantrone: a CALGB phase I study

Twenty-one patients with relapsed or refractory acute myeloid leukemia (AML) were treated with mitoxantrone (12 mg/m2/day, days 1-3) and diaziquone (continuous infusion days 1-5). The dosage of diaziquone was increased for sequential cohorts of seven patients from 20 mg/m2/day to 24 mg/m2/day, and finally to 28 mg/m2/day to determine the maximum tolerated dose for this chemotherapy combination. Myelosuppression was the dose-limiting toxicity. The median time to recovery of blood counts was greater at the highest dose of diaziquone (48 days) than at the lower two doses (31 and 28 days). Other toxic effects were minimal. Overall, 9/21 (43%, 95% confidence interval, 0.22 to 0.66) patients achieved complete remission. We conclude that this combination of drugs shows sufficient antileukemic activity with acceptable toxicity to warrant further trials.     

Continuous-infusion cyclophosphamide plus vincristine, cytosine-arabinoside and prednisone for refractory acute lymphoblastic leukemia in adults.

BACKGROUND. Despite more aggressive salvage regimens, the prognosis of refractory acute lymphoblastic leukemia (ALL) is still poor. Hence, alternative approaches are warranted in heavily pretreated patients. Some studies suggest the enhancement of cyclophosphamide (CY) activity when given by continuous infusion. METHODS. To evaluate the effectiveness of this scheduling in refractory ALL, we treated 15 adult patients (4 primary resistant, 11 relapsed and refractory to salvage regimens) with a seven-day course of CY 350 mg/m2/day by continuous i.v. infusion, associated with vincristine, cytosine-arabinoside and prednisone. RESULTS. The median time for hematologic recovery was 18 days, with negligible extramedullary toxicity. Two patients died while aplastic, 3 were non responders, 10 (66%) achieved complete remission after the first cycle. The response duration ranged from 5 to 32 (median 14) weeks, and the median survival of responders was 23 weeks. It is noteworthy that half of the responding patients had been resistant to prior CY in different schedules and other drug combinations. CONCLUSIONS. These data seem to confirm that CY exerts its best antineoplastic activity by continuous infusion.     

High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias

The aim of the study was to evaluate the antileukemic effectiveness and toxicity of high-dose hydroxyurea (HHY) and to assess its acute toxicity. Between August 1997 and October 1998, 12 consecutive adult patients (>18 years) with high-risk acute myeloid leukemia (AML) (four patients in first early relapse, seven patients with secondary AML, and one patient with de novo AML concomitant to a lymphoproliferative disorder) were enrolled to receive a single course of HY (100 mg/kg per day) until bone marrow aplasia or for a maximum of 30 days. Of the 12 patients, 5 (41.6%) achieved complete remission (CR), 1 achieved partial remission (PR), 4 were resistant to treatment, and 2 died during induction from infection. No patient with relapsed AML achieved CR, while it was achieved by five of eight patients with secondary AML at diagnosis; five of six MDR1+ patients achieved CR. As concerns follow-up of the CR patients, one did not receive any further treatment and died in CR from pulmonary aspergillosis, and one with a concomitant chronic lymphocytic leukemia (CLL) received two courses of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) regimen with disappearance of the clonal Ig rearrangement, but relapsed after 11 months and died from pneumonia. The remaining three patients were consolidated with two courses of high-dose cytosine arabinoside (AraC), followed by peripheral blood stem cell transplantation (PBSCT) in one patient. One of them relapsed after 3 months, while the other two are still in continuous complete remission (CCR) after 16 and 28 months, respectively. This study has demonstrated the safety and efficacy of HHY in inducing CR in AML patients with unfavorable prognosis. Despite the small number of patients, these encouraging results warrant further studies.     

Long-term oral administration of etoposide (VP-16) for the patients with refractory or relapsed acute non-lymphocytic leukemia

We investigated the efficacy of oral etoposide (VP-16) for the patients with acute non-lymphocytic leukemia (ANLL) in relapse or refractory to the standard chemotherapy. Patients were given etoposide orally at the dose of 50 mg/body/day on consecutive days until the leukemic cells in the bone marrow were reduced less than 5%. The duration of administration of oral etoposide ranged from 16 days to 50 days (average 30 days). Seven patients were given very low dose cytosine arabinoside (5 approximately 10 mg X 2/day i.s.c.) combination with oral etoposide. Six patients (66.7%) out of 9 achieved complete remission (CR) and 3 patients had no response. Adverse effects such as abdominal discomfort and appetite loss were observed in 3 patients, but they were mild and tolerable. The duration of CR ranged from 2 to 24 (+) months, and the median CR duration is 7 months. The over all CR rate (66.7%) in this group of patients with refractory or relapsed ANLL were encouraging. Further studies, however, are needed to evaluate the efficacy of long term oral administration of etoposide for the patients with leukemia.     

Mitoxantrone and continuous infusion of cytosine arabinoside in refractory and relapsed acute lymphoblastic leukemia.

Twenty adult patients with relapsed or refractory acute lymphoblastic leukemias (ALL) received a regimen employing two courses of mitoxantrone 12 mg/m2 by rapid intravenous infusion on days 1, 2 and 3 and cytosine arabinoside (ARA-C) 200 mg/m2/day by continuous infusion on days 1-7. Complete remission (CR) was achieved in 10 of 20 (50%) patients (3 refractory and 7 relapsed). Median duration of CR was 5 months (range 2-9). The treatment was associated with minimal extrahematologic toxicity, with no cardiac toxicity. Our results are nearly in line with therapeutic responses obtained with regimens employing megadose therapy (HD ARA-C). Because of acceptable toxicity, mitoxantrone plus continuous infusion of a standard dose of ARA-C could be considered for relapsed of refractory ALL patients eligible for an intensive therapeutic approach (bone marrow transplantation) after a second CR.     

Etoposide in combination with cytarabine, doxorubicin, and 6-thioguanine for treatment of acute nonlymphoblastic leukemia in a protocol adjusted for age

Etoposide combined with cytarabine, doxorubicin, and 6-thioguanine was used to treat 34 patients with acute nonlymphoblastic leukemia (ANLL) in an age-adjusted protocol, with patients greater than 50 years old receiving fewer days of therapy. Complete remissions (CR) occurred in 85% of all patients (29 of 34 patients). Patients less than or equal to 50 years of age achieved a 94% CR rate (17 of 18 patients) compared to a 75% CR rate (12 of 16 patients) in older patients. Duration of remission was less for those greater than 50 years of age. The remission rate for primary ANLL was 86% (19 of 22 patients) and for secondary or relapsed ANLL was 83% (ten of 12 patients). Thus, this is effective therapy for primary and secondary or relapsed ANLL. When the days of therapy are reduced for older patients' age, the remissions are fewer and less durable.     

Daunorubicin in patients with relapsed and refractory acute nonlymphoblastic leukemia previously treated with anthracycline

While the efficacy of daunorubicin (DNR) in first induction of patients with acute nonlymphoblastic leukemia (ANLL) has been well documented, little data are available concerning the activity of DNR in patients with relapsed and refractory ANLL previously treated with anthracycline. We administered DNR (60 mg/m²/day for 3-5 days) in 21 patients with relapsed (n=12) or refractory (n=9) ANLL previously treated with anthracycline. The general response rate was 48%, with a complete response (CR) rate of 38%. Five of 12 patients with relapsed ANLL and 3 of 9 patients with refractory ANLL achieved CR. Among these cases with CR in refractory ANLL, the evolution of one patient is particularly illustrative since he had received previously a large cumulative dose of anthracycline (540 mg/m²) and has been shown to be refractory to high-dose cytosine arabinoside. This study suggests that previous administration of DNR or adriamycin does not Induce significant resistance to anthracycline: DNR appears to be almost as efficient in patients with relapsed and refractory ANLL previously treated with anthracycline as in first induction.     

Low-dose arabinosyl cytosine in acute leukemia after a myelodysplastic syndrome and in elderly leukemia

Low-dose arabinosyl cytosine (ARA-C) was tested in 15 patients with acute leukemia after a myelodysplastic syndrome (MDS) and in six elderly patients with acute nonlymphoid leukemia (ANLL). The drug was given subcutaneously at 10 mg/m2, every 12 hr for 2 weeks, every 28 days. The overall response rate was 19% (one complete remission, three partial responses), and the median duration of response was 4 months. No particular features at diagnosis were predictive of response. Pancytopenia and marrow hypoplasia occurred after 44 (78%) of 56 courses of therapy and were more severe in nonresponders. Four patients died during the aplasia following ARA-C therapy. Subcutaneous low-dose ARA-C was of limited benefit and bore a noticeable hematologic toxicity.     

Liposomal daunorubicin (DaunoXome) for treatment of poor-risk acute leukemia

Toxicity limits the use of anthracyclines in elderly sick patients and in heavily pretreated patients. Since the liposomal preparation of daunorubicin (DNR) (DaunoXome, or DNX) is expected to be less toxic than conventional DNR, we tested DNX combined with high-dose arabinosyl cytosine (HDAC) in 42 adult poor-risk acute leukemia patients. Thirty-one patients had acute non-lymphocytic leukemia (ANLL). Of these, 12 patients were newly diagnosed but were not eligible for standard induction treatment, 13 were in first relapse, and 6 were in second or subsequent relapse. Eleven patients had acute lymphocytic leukemia (ALL), in first (eight cases) or second (three cases) relapse. DNX was given i.v. in three doses of 80 or 100 mg/m(2) each (days 1-3) by a 60-min infusion in glucose 5%, followed by a 4-h infusion of HDAC 2 g/m(2) (days 1-5). Among 31 ANLL patients there were 16 (51%) complete remissions (CR), 5 deaths during induction, and 10 failures. Among 11 ALL patients there were 10 CRs and 1 failure. The response rate was not affected by the overexpression of MDR-related proteins (PgP, MRP-1, and LRP). Non-hemopoietic toxicity was negligible, with no intestinal toxicity and only one case of gram-negative bacteremia. We conclude that DNX, in combination with HDAC, is an effective treatment for poor-risk adult AL. Because of the low non-hematologic toxicity, it can be used to reinduce remission in poor-risk patients who are candidates for allogeneic bone marrow transplantation. The high CR rate observed in ALL requires confirmation.     

Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions

The efficacy and toxicity of donor leukocyte infusions (DLI) after unrelated donor bone marrow transplantation (BMT) is largely unknown. We identified 58 recipients of unrelated DLI (UDLI) for the treatment of relapsed disease from the National Marrow Donor Program database. A retrospective analysis was performed to determine response, toxicity, and survival after UDLI and to identify factors associated with successful therapy. UDLI was administered for relapsed chronic myelogenous leukemia (CML) (n = 25), acute myelogenous leukemia (AML) (n = 23), acute lymphoblastic leukemia (ALL) (n = 7), and other diseases (n = 3). Eight patients were in complete remission (CR) before UDLI, and 50 were evaluable for response. Forty-two percent (95% confidence interval [CI], 28%-56%) achieved CR, including 11 of 24 (46%; 95% CI, 26%-66%) with CML, 8 of 19 (42%; 95% CI, 20%-64%) with AML, and 2 of 4 (50%; 95% CI, 1%-99%) with ALL. The estimated probability of disease-free survival (DFS) at 1 year after CR was 65% (95% CI, 50%-79%) for CML, 23% (95% CI, 9%-38%) for AML, and 30% (95% CI, 6%-54%) for ALL. Acute graft-versus-host disease (GVHD) complicated UDLI in 37% of patients (grade II-IV, 25%). A total of 13 of 32 evaluable patients (41%) developed chronic GVHD. There was no association between cell dose administered and either response or toxicity. In a multivariable analysis, only a longer interval from BMT to relapse and BMT to UDLI was associated with improved survival and DFS, respectively. UDLI is an acceptable alternative to other treatment options for relapse after unrelated donor BMT. (Blood. 2000;95:1214-1221)     

Phase II study of methotrexate,vincristine, pegylated‐asparaginase,and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia

Newer approaches are needed for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). Asparaginase‐based regimens are active in the treatment of pediatric ALL and may be important in salvage therapy for adult patients. We conducted a pilot trial combining methotrexate, vincristine, PEGylated‐asparaginase, and dexamethasone (MOpAD) in adults with relapsed or refractory ALL. We added tyrosine kinase inhibitors in patients with Philadelphia chromosome positive (Ph+) ALL and rituximab in patients with CD20 positive B‐cell ALL. Among 37 patients treated (median age 42 years; median 2 prior therapies), the complete remission (CR) rate was 28% and an overall response rate (ORR) was 39%. The median CR duration was 4.3 months. Patients with Ph+ ALL had CR and ORR of 50% and 67%, respectively and the CR and ORR in patients with T‐cell leukemia were 45% and 56%, respectively. The median survival in patients with CR/CRp was 10.4 versus 3.4 months in nonresponders (P = 0.02). The most common grade 3 or 4 nonhematologic toxicities were elevations in bilirubin and transaminases, nausea, peripheral neuropathy, and hyperglycemia, which were managed with supportive care, dose adjustments, and interruptions. Am. J. Hematol. 90:120–124, 2015. © 2014 Wiley Periodicals, Inc.     

Adult leukemia developing after aplastic anemia: report of 8 cases

481 cases of adult leukemia (115 acute lymphoblastic leukemia, ALL, and 366 acute nonlymphoid leukemia, ANLL) diagnosed at the Hematology Division of Pavia between 1976 and 1985 were reviewed to evaluate how many patients had an aplastic presentation. In 8 cases (1.6%) typical marrow hypoplasia preceded overt leukemia. At the leukemic transformation, the morphological and immunological findings were diagnostic for non-T non-B ALL in 2 cases, for ANLL in 5 cases (2 M1, 2 M2, 1 M5) and for Ph'-negative chronic granulocytic leukemia in 1 case. Median survival from the onset of leukemia was 5 months. In a certain proportion of cases aplastic anemia may be considered as a preleukemic state with a low propensity to develop into acute leukemia.     

BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission

Twenty-one acute myelogenous leukemia (AML) patients were submitted in second remission (II CR) to BAVC conditioning regimen followed by unpurged ABMT. Transplant was done after a median of 2 months from II CR (range, 1 to 13). Median first remission (I CR) duration was 16 months (range, 1-35). Conditioning regimen was well tolerated, with no major extra-medullary toxicity. One patient died during aplasia from fungal sepsis. Of the 20 evaluable patients, nine relapsed after a median time of 6 months (range, 2 to 18). Eleven patients are in continuous complete remission (CCR) after a median follow-up of 40 months (range, 24 to 63). The duration of II CR has exceeded the duration of I CR in all patients in CCR. Projected probability of disease-free survival is 52% at 63 months.     

Intensive salvage chemotherapy for primary refractory or first relapsed adult acute lymphoblastic leukemia: results of a prospective trial.

BACKGROUND AND OBJECTIVE: Adults with primary refractory or relapsed acute lymphoblastic leukemia (ALL) have a very poor prognosis with current salvage chemotherapies. Complete remissions (CR) can be obtained with intensive regimens in 40-60% of cases, but they are short-lived. In an effort to obtain high CR rates and prolong their duration and achieve long-term survival in a substantial number of patients, we designed an intensive combination salvage regimen (RELAL-88). In this protocol, chemotherapy was to be followed by an allogeneic or autologous stem cell transplant (SCT) within three months from CR. DESIGN AND METHODS: Forty-five patients with primary refractory (n=17) or first relapsed ALL (n=28) were treated with the RELAL-88 five-day induction regimen comprising vindesine, mitoxantrone, cyclophosphamide, intermediate-dose Ara-C, prednisolone and methotrexate. Twenty-eight patients received granulocyte colony-stimulating factor (G-CSF), 16 patients from day 6 (early G-CSF group) and 12 from day 14 of therapy (delayed G-CSF group). RESULTS: Thirty-four patients (74%) achieved CR (95% CI 60-87), two died in aplasia due to infection and nine were non-responders. No pretreatment variable analyzed was predictive of the chance of obtaining CR. Recovery of neutrophils occurred at a median of 29 days from the start of chemotherapy without G-CSF and 20 days with G-CSF (p = 0.005), without differences between the early and late G-CSF groups. Non-hematologic side effects were usually well tolerated and consisted mainly of infections and mucositis. Twenty-three of 34 patients (68%) who achieved CR reached the planned SCT (nine autologous and 14 allogeneic). The median overall survival was 5.7 months, and the median disease-free survival for those achieving CR was 4.6 months. Of the variables analyzed for their influence on overall survival among the 34 patients who achieved CR, only the availability of an HLA-compatible sibling was associated with a prolonged survival (p = 0.03). INTERPRETATION AND CONCLUSIONS: The RELAL-88 intensive salvage regimen produces a very high rate of CR in poor-risk adult ALL. Non-hematologic toxicities were tolerable, and most eligible patients could undergo the planned SCT. G-CSF significantly shortened the period of neutropenia by about eight days, irrespective of whether it was started early or late after chemotherapy. However, as with other currently available salvage therapies, remissions were short-lived, and more effective post-remission treatment strategies are needed. In our experience, only allogeneic SCT offered the chance of long-term survival.