Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study

Abstract With modern risk-adapted multi-agent chemotherapy, complete remission (CR) is obtained in the majority of children with acute lymphoblastic leukemia (ALL) and long-term survival free from disease can be expected in more than 70% of them. However, the prognosis of the patients without CR (induction failure; IF) has been dismal. We conducted a prospective study of F-protocol followed by a hematopoietic stem cell transplantation (SCT) in patients with IF. Purpose: To evaluate the efficacy and safety of the treatment strategy adopted in the JACLS ALL F-protocol. Patients and methods: Between April 1997 and March 2005, 1,254 patients with newly diagnosed ALL (excluding mature B-cell ALL) were enrolled on two consecutive JACLS ALL protocols (ALL-97 and ALL-02). Excluding induction death, 19 (1.6%) out of 1,207 patients with non-Ph+ ALL and 9 (30%) out of 30 patients with Ph+ ALL could not achieve CR following four- or five-drug induction chemotherapy. Among them, 25 patients in total were entered the study with guardian’s written consent. F-protocol consisted of the AML oriented re-induction chemotherapy (3 days of 8 mg/m2 MIT, 500 mg/m2 CA, and 40 mg/m2 PSL, followed by 3 days of 200 mg/m2 VP16, CA, and PSL a week later), four block consolidation therapy consisting of two alternative regimens A and B (A: HD-DEX, VP16, CA, MIT, B: HD-MTX, ASP, PSL, CA, THP-ADR) and maintenance therapy. Patients with CR were scheduled to receive SCT after the second consolidation therapy before the maintenance therapy. Transplant procedures depended on the institute. Results: Following the re-induction therapy, 15 of 16 patients with non-Ph+ ALL (93.8%) achieved CR and 13 (86.7%) of them had continued CR until 27th week of treatment (CCR), which was the expected limiting time of SCT. Eight of 11 patients receiving SCT at the first CCR are alive. Two of 13 patients with CCR did not receive SCT by a physician’s decision, and relapsed during maintenance therapy. However they are alive following SCT in second CR. Five-year overall survival rate (OS) and event free survival rate for all 16 cases was 53% and 32.8%, respectively. Estimated five-year OS for patients receiving SCT at the first CCR was 59.7%. On the other hand, only 3 of 9 patients with Ph+ ALL (33.3%) achieved CR. No patients without response to re-induction therapy could achieve CR by any subsequent chemotherapy, but one success with SCT. Among 3 patients attaining a CR with re-induction therapy, 2 could continue CR and underwent SCT. One is alive in CCR and the other deceased from TRM. The other patient, relapsed during consolidation therapy, underwent SCT with success. Five-year OS for all 9 patients with Ph+ ALL was 33.3%. Concerning about adverse events of F-protocol, there was only one non-hematological toxicity NCI-CTC grade 4, which was pancreatitis due to ASP. Conclusions: F-protocol could produce a high remission induction rate in non-Ph+ ALL, but not in Ph+ ALL. Improved outcome of non-Ph+ ALL patients with IF seemed to be obtained with F-protocol timely followed by SCT.

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A Comparison of Two Induction Regimens for Older Patients with Acute Lymphoblastic Leukemia: Daunorubicin, Vincristine and Prednisone (DVP) is Worth Considering

Blood ◽

10.1182/blood.v116.21.3252.3252 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3252-3252

Author(s):

Daniel Landsburg ◽

David Porter ◽

Edward Stadtmauer ◽

Alison Loren ◽

Donald Tsai ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Maintenance Therapy ◽

Induction Therapy ◽

Older Patients ◽

Lymphoblastic Leukemia ◽

Complete Response ◽

High Dose ◽

Treatment Groups ◽

Social Security Death Index

Abstract Abstract 3252 Background: The prognosis for older patients with newly-diagnosed acute lymphoblastic leukemia (ALL) is generally poor, although a limited number of studies suggest that these patients can experience favorable outcomes when treated with standard intensive chemotherapy. However, a comparative analysis of curative regimens has not been performed to date. Here, we describe outcomes in patients diagnosed with ALL at age ≥60 who received induction at our institution with either hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyperCVAD) or daunorubicin, vincristine and prednisone (DVP). Methods: Of the 44 patients diagnosed with ALL at age ≥60 who were treated at the University of Pennsylvania between July 2003 and June 2009, 38 received either hyperCVAD (n=24) or DVP (n=14). Induction regimens were chosen at the discretion of the treating physician. Patients in the hyperCVAD group received a median of 6 (range 1–8) cycles. Patients in the DVP group received a full course of induction therapy following the regimen used in the ECOG 2993/UKALL XII protocol with a majority receiving second induction, intensification and consolidation therapy. L-asparaginase was omitted from DVP therapy for all but 2 patients. Assessment for response or relapse was performed primarily via bone marrow biopsy as clinically indicated. If lost to follow-up, patients with previously documented remission were considered to remain in remission through the time of their last normal complete blood count. All deaths were confirmed through the Social Security Death Index. Categorical data was analyzed via the Fisher's exact test and survival times were calculated via Kaplan-Meier plots. Results: Table 1 reports baseline characteristics at diagnosis for patients in the hyperCVAD and DVP groups. Tables 2 and 3 report the rates of complete response (CR) and relapse as well as median progression free survival (PFS) and median overall survival (OS) for the two treatment groups. The median length of follow-up was 12.5 months for the hyperCVAD group (range 3–70) and 24 months for the DVP group (range 4–136). Five-year survival was 4% for hyperCVAD patients and 36% for DVP patients (p=0.019). No deaths occurred within the initial 2 months of treatment in either group. Maintenance chemotherapy was received by 50% of hyperCVAD patients and 70% of DVP patients. Of the Ph(+) patients in who received hyperCVAD, 75% received a tyrosine kinase inhibitor (TKI) with induction therapy and 50% with maintenance therapy. Of the Ph(+) patients in who received DVP, 29% received a TKI with induction therapy and 83% with maintenance therapy. All Ph(+) patients who experienced OS greater than the median OS for Ph(+) patients within their respective treatment groups received a TKI. These results did not achieve statistical significance unless otherwise noted. Conclusions: Older patients diagnosed with ALL can enjoy prolonged survival when treated with intensive induction regimens. While this has been previously described in patients receiving hyperCVAD, our analysis indicates that patients diagnosed with ALL at age ≥60 treated with DVP may experience longer OS compared to those treated with hyperCVAD despite an apparent lower rate of complete response and similar rate of relapse. Additionally, Ph(+) patients within this population may experience similar or better outcomes than Ph(-) patients when treated with either regimen, possibly related to the use of TKIs. Prospective trials are warranted to more rigorously evaluate these induction therapies in the older ALL population. Disclosures: No relevant conflicts of interest to declare.

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Receipt of Maintenance Therapy Is Most Predictive of Survival in Older Acute Lymphoblastic Leukemia Patients Treated with Intensive Induction Chemotherapy Regimens.

Blood ◽

10.1182/blood.v120.21.2600.2600 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2600-2600

Author(s):

Daniel J. Landsburg ◽

Edward A. Stadtmauer ◽

Alison W. Loren ◽

Steven C. Goldstein ◽

Noelle V. Frey ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Maintenance Therapy ◽

Induction Therapy ◽

Lymphoblastic Leukemia ◽

Intensive Therapy ◽

Small Sample ◽

Hazard Ratio ◽

High Dose ◽

Cox Regression Analysis

Abstract Abstract 2600 Background: Older patients diagnosed with acute lymphoblastic leukemia (ALL) receiving intensive induction therapy often suffer from poor outcomes due to therapy-related toxicity and high rates of relapse. We previously reported that patients age ≥60 diagnosed with ALL and treated at our institution with either hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyperCVAD) or daunorubicin, vincristine and prednisone (DVP) induction therapies achieved comparable rates of survival. Now with longer follow-up and further analysis, we describe additional outcomes and factors predictive of survival in this patient population. Methods: Thirty-seven patients diagnosed with ALL at age ≥60 and treated at the University of Pennsylvania between July 2003 and June 2011 who received induction therapy with either hyperCVAD (≥1 A+B cycle) or DVP (phase I+II) were analyzed. HyperCVAD was administered as first described at the MD Anderson Cancer Center and DVP per the ECOG 2993/UKALL XII protocol. Therapy adjustments and bone marrow biopsy to confirm remission were performed at the discretion of the treating physician. Almost all Philadelphia chromosome (Ph) positive patients received a tyrosine kinase inhibitor. Event-free survival (EFS) was defined as the time from diagnosis to either relapse or death from any other cause. Results: Table 1 describes baseline characteristics. Table 2 describes outcomes. If achieved, morphologic remission was recognized upon the first bone marrow assessment performed while on therapy, which occurred after a median of 4 (2 A+B) cycles of hyperCVAD and by completion of phase II induction of DVP. EFS and overall survival (OS) trended in favor of DVP. HyperCVAD patients were more likely to complete intensive therapy but less likely to receive maintenance therapy, and more likely to relapse with the majority of relapses occurring off active treatment. Primary reasons for not starting or stopping maintenance therapy were infections and cytopenias. Relapsed disease was the most frequent cause of death. Table 3 describes univariate Cox regression analysis. Receipt of maintenance therapy demonstrated the strongest association with survival (p=0.0001, hazard ratio 0.06 for EFS; p=0.0002, hazard ratio 0.05 for OS). Valid multivariate analysis could not be performed due to small sample size. Conclusions: In older ALL patients treated with aggressive induction therapies and achieving remission, receipt of maintenance therapy appears to be most predictive of EFS and OS. Outcomes in the DVP and hyperCVAD groups were similar although a trend towards prolonged survival in the DVP group was seen, which may be explained by a lower rate of relapse due to a higher likelihood of remaining on therapy over time. Our findings suggest that these patients may benefit from attenuated courses of intensive initial therapy in order to avoid developing toxicities that may prohibit tolerance of prolonged maintenance therapy. Disclosures: No relevant conflicts of interest to declare.

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