2010: Focus on Hematologic Malignancies

This year's American Society of Clinical Oncology meeting featured a highly select lineup of sessions dealing with hematologic malignancies. Over the past decade, we have seen much progress in the treatment of blood cancers, but continuing improvement of outcomes will depend on the identification of novel therapies and the accurate determination of which patients will benefit from these therapies. Meetings such as these generate the necessary synergies that bring promising new agents from bench to bedside. Below are several presentations that highlight a fraction of the important work presented at 2010 meeting.

Allogeneic Transplants After Hyper-CVAD plus Imatinib Boost Ph+ ALL Survival
Abstract: 6506

In the oral abstract session, Deborah A. Thomas, MD reported study results on behalf her colleagues that found that allogeneic transplantation confers a significant survival advantage, particularly among younger patients, when treating Philadelphia chromosome-positive acute lymphoblastic leukemia with a regimen that adds imatinib to hyper-CVAD chemotherapy.

Dr. Thomas noted that among patients aged 40 years or younger with de novo disease, the 3-year overall survival rate was 90% in those who went on to allogeneic stem cell transplant, compared with 33% for those who did not undergo transplant (P = .05). The study also showed that the addition of imatinib appears to significantly improve outcomes for patients with Ph+ ALL. Dr. Thomas reported follow-up data on 54 patients with imatinib-naive (39) or minimally treated (15) disease enrolled at her center in 2001-2006. The patients received a combination of imatinib plus hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone).

The first 20 patients received a syncopated regimen of 400 mg imatinib for the first 14 days of each of eight intensive cycles of hyper-CVAD, alternating with high-dose methotrexate and cytarabine and followed by a maintenance phase with imatinib 600 mg in combination with monthly vincristine and prednisone. This was interrupted with intensification phase hyper-CVAD and imatinib at 6 and 13 months.

Dr. Thomas said that when they determined that imatinib did not add significant toxicities, the protocol was modified and all remaining patients received imatinib at a standard intermediate dose on a continual basis beginning with consolidation chemotherapy. The imatinib dose was increased further as tolerated during the maintenance phase, and maintenance was extended for an additional 12 months with monthly vincristine and prednisone, followed by imatinib thereafter.

In all, 39 patients had de novo disease at enrollment, 6 had refractory disease after one course of prior therapy, and 9 were in complete remission following a prior course. The complete remission rate for the 39 patients with de novo disease was 92% (36 of 39), comparable to that of 50 historical controls who received hyper-CVAD alone. However, the imatinib-treated patients were more likely to achieve complete remission after one course of therapy (85% vs. 70% for controls).

All six patients with primary refractory disease who were treated with hyper-CVAD plus imatinib had complete remissions, and nine patients who were in complete remission following a prior course of therapy also remained in remission.

The failures among the previously untreated patients included one complete remission in the absence of platelet recovery, one partial remission, and one early death from sepsis. The molecular complete response rate confirmed by polymerase chain reaction was 52%.

At a median follow-up of 77 months (with the longest follow-up past 101 months), six patients had experienced a relapse on program. Five of the relapses occurred at 8-21 months of follow-up, and one at 42 months.

In five of these patients, the relapse occurred after a change in TKI therapy for either persistent Philadelphia chromosome or increasing BCR-ABL transcripts. Two of the relapses occurred after allogeneic stem cell transplant without imatinib maintenance. Many of the patients in relapse were successfully salvaged with hyper-CVAD and dasatanib (Sprycel).

Therefore, it appears that Philadelphia-positive ALL patients under the age of 40 may benefit from an allogeniec transplant after a hyper-CVAD/imatinib regimen. This study was hampered by the small number (10) of patients < 40 who underwent an allogeniec BMT. Additional follow-up of these patients will be of interest.

A new study reported that bosutinib shows clinical efficacy in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase, with complete cytogenetic response rates of 50% in a multinational study, investigators reported.

According to lead author, Jorge E. Cortes, MD, at 24 months of follow-up, 77% of imatinib (Gleevec)-resistant patients and 86% of imatinib-intolerant patients who were treated with the investigational drug were alive without evidence of disease progression, and median progression-free survival has not yet been reached in either group.

Moreover, responses to second-line therapy with bosutinib (SKI 606) were seen across a variety of BCR-ABL mutations, and the drug had a favorable toxicity profile, with manageable, self-limiting gastrointestinal adverse events, low rates of hematologic toxicity, and minimal fluid retention.

Imatinib resistance was defined as no complete hematologic response by 3 months; cytogenetic response by 6 months; or major cytogenetic response by 12 months; or by a loss of response. Imatinib intolerance was defined as grade 4 hematologic toxicity lasting more than 7 days; grade 3 or greater nonhematologic toxicity; or persistent grade 2 toxicity not responding to adequate management and/or dose adjustments.

The median patient age was 52 years, the median time from diagnosis was 4 years, and the median duration of prior imatinib therapy was 2.3 years. In all, 202 patients were imatinib resistant, and 92 were imatinib intolerant.

The patients were treated with a median of 13.7 months of bosutinib at a median dose intensity of 454.1 mg/day. The median follow-up was 23.8 months at the time of data cutoff (Feb. 22, 2010). About three-fourths of patients had dose interruptions, which were attributable to toxicities, lack of compliance, or other factors. Dose escalations up to 600 mg were allowed for the 33 patients who had an inadequate response on the 500-mg starting dose.

Among 109 patients who did not have hematologic responses at baseline (that is, no hematologic response to imatinib), 102 had a response to bosutinib, and 99 of these response were complete responses. Major cytogenetic responses were seen in 136 of 214 patients who did not have cytogenetic responses to imatinib, and 106 of these patients had complete cytogenetic responses. Major molecular responses were seen in 79 of 151 patients who lacked such responses at baseline, and complete molecular responses were seen in 49.

In all, 97% of imatinib-intolerant patients had a hematologic response, and all were complete responses. Overall responses occurred in 92% of imatinib-resistant patients; 88% were complete responses. Complete cytogenetic responses were seen in 59% of intolerant patients and in 46% of resistant patients, and complete molecular responses were seen in 40% and 30%, respectively.

The responses occurred rapidly, with median time to complete hematologic response occurring within 1 month. Median time to complete molecular response was 6.3 months, and to complete cytogenetic response was 12.3 months. The response rate curves continue to rise into the second and third years of therapy, Dr. Cortes said.

In all, 19 different mutations were identified in 43 of 96 patients tested thus far. The mutations, except forT315I, did not appear to affect response rates, with 86% of evaluable patients with any mutation having a complete hematologic response, and 72% having a major molecular response. There were no responses in patients with T315I.

Treatment-emergent grade 3 or 4 adverse events included diarrhea and rash (each occurring in 9% of patients), vomiting in 3%, and nausea and asthenia in 2% each. Diarrhea was usually self-limited. In all other categories, the incidence of grade 3 or 4 events was 1% or lower. Hematologic laboratory abnormalities include thrombocytopenia in 24%, neutropenia in 16%, and anemia in 12%.

Nearly half of all patients discontinued therapy, primarily because of adverse events (19%). Disease progression led to discontinuations in 5% of imatinib-intolerant patients and 15% of resistant patients. Other reasons for discontinuation included unsatisfactory responses, patient or investigator request, or being lost to follow-up. There were five deaths among the resistant patients, but none in the intolerant group.

A phase III, randomized study that pits bosutinib against imatinib in newly diagnosed patients with CML in chronic phase has recently completed accrual, and results are expected at the end of 2010, Dr. Cortes said.

Experimental Agent Shows Promise in Advanced Hodgkin's Lymphoma
Abstract 8007

According to interim data from a multinational phase II trial, the experimental drug panobinostat appeared to show activity against relapsed and refractory Hodgkin’s lymphoma in most of the heavily pretreated patients.

Lead author, Anna Sureda, MD, noted that one-fourth of patients with relapsed/refractory Hodgkin's lymphoma following autologous stem cell transplant had either a complete or partial response to monotherapy with panobinostat (LBH589), and 60% had stable disease.

Of 129 patients, 4 (3%) had a complete response to panobinostat, 29 (22%) had a partial response (defined as a reduction of tumor size by a least 50%), and 111 were deemed to have disease control (defined as a combination of complete and partial responses and stable disease).

Based on early data, investigators at 45 sites in 13 countries enrolled 129 patients, who had a confirmed history of Hodgkin's lymphoma and progressive disease after high-dose chemotherapy and autologous stem cell transplant, into the open-label phase II study.

The patients could have received no more than five prior systemic regimens, but previous allogeneic transplants were allowed. The patients also had to have at least one site of measurable nodal disease at baseline and no prior deacetylase inhibitor therapy.

Panobinostat 40 mg is given orally three times per week in a 21-day treatment cycle, with some patients receiving treatment for more than 1 year so far. Dose delay and dose modifications are allowed for management of adverse events. Responses are assessed every two cycles by CT and MRI.

The primary end point of the trial is objective response rate. Secondary end points are time to response, duration of response, progression-free survival, safety and tolerability, and overall survival. All 129 patients were available for the interim analysis.

In all, 26% of patients (33) had an objective response, 71% had some degree of tumor reduction on study, and 22% met the partial response criteria of a 50% or greater reduction. Four patients (3%) had complete disappearance of tumor on imaging studies. The median time to response for all patients was 7 weeks (range, 4-51 weeks), the median estimated duration of response was 7.2 months, and the median progression-free survival by Kaplan-Meier analysis was 5.9 months.

As in the phase I study, the most common toxicity was grade 3/4 thrombocytopenia, which occurred in 100 patients, but only 7 of these patients discontinued the study medication because of this adverse event. Other common events included grade 1 or 2 diarrhea, nausea, and fatigue.

A sub-analysis of the 33 responders showed a median of four prior chemotherapy regimens. Of this group, 26 (79%) had received radiotherapy, and 15 (45%) had no response to their most recent therapy. 

Bosutinib Induces High Response Rates in Imatinib-Resistant, -Intolerant Patients
Abstract: 6502