Wednesday, October 26, 2011

Lenalidomide as frontline treatment in the elderly

An important paper was published in Blood in September of the use of lenalidomide as front line therapy for elderly patients with CLL.

Despite the fact that two-thirds of the patients diagnosed with CLL are older than 65 there is no frontline therapy for elderly patients that is superior to any other.

The GCLLSG conducted a trial randomizing 193 patients over-65 to fludarabine or chlorambucil. Although there were higher response rates with fludarabine PFS and OS wee identical. Hillmen et al compared alemtuzumab and chlorambucil. Again, despite a higher overall response rate observed with alemtuzumab in a subgroup analysis of 105 patients older than 65 years, median PFS was only 12.5 months in both treatment arms. In both those trials suboptimal doses of chlorambucil were used.

Chemoimmunotherapy combinations like FCR have led to improvements in survival in younger patients with CLL and have become the standard of care but when offered to older patients, there are higher rates of treatment-related toxicities. Patients older than 70 years have an increased rate of myelotoxicity and are less likely to complete 6 cycles of therapy. Dose-reduced purine analog trials, such as the “FCR-Lite” and PCR, have been developed to reduce myelotoxicity and improve tolerability in the elderly; but there are few comparative data.

In this age group, cure is usually not the option, but longer remissions are. In addition, the impact of treatment on daily life activities and the intensity of monitoring requirements are particularly important to this population. Because of convenient oral administration and favorable toxicity profile, chlorambucil is often chosen as initial therapy for elderly patients.

Based on the efficacy observed with lenalidomide in patients with relapsed or refractory disease, MD Anderson designed a phase 2 trial to study lenalidomide in elderly patients requiring initial treatment. In vitro evidence for an immunostimulatory effect of lenalidomide on T-lymphocytes made this particularly appealing for elderly patients who are especially vulnerable to myelosuppressive and immunosuppressive treatments. The convenient oral route of administration of lenalidomide is also particularly attractive.

Sixty untreated patients with symptomatic CLL were enrolled in this phase 2 prospective study. All patients were age 65 years or older, and indication for treatment initiation by National Cancer Institute (NCI 2008) Working Group criteria.1Entry criteria also required a performance status of 0 to 3, and serum creatinine, bilirubin, and alanine transaminase were required to be less than or equal to twice the upper limit of normal. Patients were able to participate on this study regardless of absolute neutrophil or platelet count.

Pretreatment evaluation included medical history, physical examination, complete blood count with differential and serum creatinine, electrolytes, albumin, calcium, uric acid, LDH, ALT, serum Ig levels, β2-M levels, and peripheral T-cell lymphocyte subset analysis by flow cytometry were also measured. Bone marrow aspiration and biopsy were performed before therapy, including infiltration assessment, immunophenotype by flow cytometry, IGHV gene mutaions, and Zap-70 expression by flow cytometry. Standard metaphase karyotype analysis and FISH. CCL3 and CCL4 protein levels were measured in peripheral blood plasma samples of 31 patients before therapy and at study assessment time points.

Patients received lenalidomide orally at the initial dose of 5 mg daily administered continuously for 56 days (cycles 1 and 2). After day 56, the dose could be titrated up by 5 mg every 28 days to a maximum dose of 25 mg/day as tolerated. One cycle of therapy consisted of 28 days of lenalidomide. Dosing of lenalidomide could be increased to optimize response as per the treating physician's discretion and in accordance with protocol guidelines. If patients did not tolerate higher doses of lenalidomide, dosing was adjusted to the highest tolerated dose. Patients deemed at high risk for thrombotic events could receive aspirin as prophylaxis. Hematopoietic growth factor support was allowed according to ASCO guidelines. Allopurinol (300 mg daily) was administered as tumor lysis prophylaxis on days 1 to 14 of cycle 1. There was no mandated antibacterial or antiviral prophylaxis. Lenalidomide dose was withheld in patients experiencing CTC grade 3 or 4 toxicities, and treatment was restarted at a reduced dose of lenalidomide on resolution of toxicity to grade 2 or lower.

Response assessment was performed using 2008 NCI criteria after the first 3 cycles of therapy and every 6 cycles thereafter. Assessment included physical examination, peripheral blood examination, bone marrow aspirate and biopsy, and lymphocyte immunophenotyping on bone marrow aspirate. CT scans were not routinely performed for response assessment. Flow cytometric assessment of bone marrow aspirate using 3-color (this is less sensitive than other centers use) flow cytometry was performed to estimate MRD by evaluating for CD5+/CD19+ lymphocytes with light-chain restriction.

Treatment was discontinued at disease progression or if patients experienced excessive toxicity. Patients who had stable disease or better after 3 cycles continued on therapy. Trial design recommended discontinuation of therapy if there was no objective evidence of response by 9 cycles of therapy, although this decision was left to treating physician's discretion. Tumor flare was defined as painful acute lymph node enlargement or lymph node enlargement with evidence of local inflammation occurring with initiation or reinitiation of therapy.

The primary endpoint of this study was PFS, which was defined as time from the start of therapy to death or progression of disease. Additional endpoints were OS, CR, and overall response rate (ORR), and nonhematologic toxicity.

The median time from diagnosis of CLL to initiation of therapy was 29 months (range, 1-202 months). The predominant indication for initiation of therapy was rapid lymphocyte doubling time for 26 patients (43%), bulky or progressive adenopathy or splenomegaly for 16 patients (27%), Rai stage III or IV CLL for 13 patients (22%), CLL related B-symptoms for 3 patients (5%), and autoimmune cytopenia for 2 patients (3%).

The median follow-up for all patients was 29 months (range, 1.5-38 months). A median of 27 cycles (range, 1-41 cycles) were administered. The median daily dose was 5 mg with a maximum tolerated dose of 20 mg and minimum dose of 2.5 mg. Lenalidomide daily dose was titrated up to 10 mg in 36 patients (60%) and to 15 mg or more in 8 patients (13%), although only 26 patients (43%) were able to continue on a dose of at least 10 mg for 2 or more cycles of therapy.

By intention to treat, the ORR was 65%, including 6 patients (10%) with CR, 3 patients (5%) with CR with residual cytopenia, 4 patients (7%) with nodular PRs, and 26 patients (43%) with partial response (PR). Four patients achieved a CR with no identifiable CLL clones by bone marrow flow cytometry (negative minimal residual disease). The median time to achievement of a PR or better was 3 months (range, 3-15 months), and the median time to achievement of CR or CR with residual cytopenia was 18 months (range, 9-27 months). Of the patients who received at least 3 cycles of therapy, most improved their response if they could tolerate further treatment.

There was no statistically significant difference in CR or ORR between patients with Rai stage or by prognostic markers, though the numbers were too small to be sure. However there were no responses among the the del 17p group.

ORR and CR rates for patients who tolerated an average dose of at least 5 mg (34 patients, ORR 82% and CR 26%) were significantly higher compared with those who received an average dose of < 5 mg (26 patients, ORR 52% and CR 3%). As a continuous variable, higher average daily dose of lenalidomide during the first 6 cycles was associated with a higher likelihood to achieve an objective response (P < .001) or CR (P = .018). Patients who could tolerate > 5 mg of lenalidomide had higher pretreatment hemoglobin level and were less likely to have 17p deletion.

At a median follow-up of 31 months, 32 patients (53%) remain on therapy with an estimated 2-year PFS of 60% (95% CI, 46%-72%). Responses to lenalidomide appeared durable with continuing therapy. Of 39 patients who achieved at least a PR, 33 patients (85%) have retained or improved their response, 5 patients (13%) have discontinued therapy in continued response because of toxicity or unrelated reasons, and 1 patient (3%) has progressed while on therapy.

PFS was significantly shorter for the 6 patients with deletion of 17p compared with patients with other FISH results (median PFS 6 months vs not reached, P = .002). Patients who experienced a tumor flare reaction of any grade had a longer PFS than patients who did not have a tumor flare reaction (median PFS not reached vs 15 months, P = .03). The average dose of lenalidomide in the first 6 cycles of therapy was also associated with PFS. At last follow-up, only 7 of 34 patients (21%) who tolerated an average dose of 5 mg or more had progressed or died compared with 16 of 26 patients (62%) who received an average dose < 5 mg (P = .003).

88% of patients were alive at a median follow-up of 31 months. Of the patients who achieved a response, 97% were alive and 85% progression-free. 3 patients died > 18 months after starting subsequent therapy after discontinuing treatment because of intolerance after < 1, 1, and 6 cycles. One patient declined further therapy after 2 cycles because of devastating social circumstances and concurrent medical issues and died 1 month later and 1 patient died after development of Richter transformation after 10 months of therapy. Two patients died of unrelated malignancies.

Twenty-eight patients discontinued treatment. Causes for discontinuation of therapy included lack or response or progressive disease (11 patients), lenalidomide intolerance without response (8 patients), lenalidomide intolerance or late adverse events (after 9 cycles of therapy) in patients with a response (4 patients), nonhematologic malignancy (3 patients), and patient preference (2 patients). Among patients intolerant of medication, reasons for discontinuation included rash (3 patients), shortness of breath (1 patient), fatigue (1 patient), infections (1 patient), fevers (1 patient), allergy (1 patient), or diarrhea (1 patient). Late adverse events (after 9 cycles of therapy) included a cerebrovascular accident, a veno-thromboembolic event, and pneumonia.

The most common toxicity was grade 3 or 4 neutropenia, which occurred in 34% of evaluable cycles. The majority of patients (83%) experienced at least one episode of grade 3 or 4 neutropenia. Grade 3 or 4 neutropenia was managed with transient interruption of therapy followed by dose reduction. Other hematologic toxicities were less common, with grade 3 or 4 thrombocytopenia and anemia occurring in only 12% and < 1% of cycles, respectively. Eight patients (13%) experienced at least one severe (grade 3 or 4) infection or neutropenic fever, including one fatal infection. In terms of grade 3 or 4 infections, there were 3 patients with pneumonia (4 episodes), 2 patients (3 episodes) with uncomplicated respiratory tract infections who received intravenous antibiotics because of neutropenia, and 3 patients admitted with febrile neutropenia (including 1 bacteremia episode). Four of the documented infections were associated with grade 3 or 4 neutropenia. Seven of the 9 severe infectious events occurred within the first 9 cycles of . Minor infections were common, with 53% of patients experiencing at least one minor infection during therapy. Minor infections included mostly upper respiratory tract infections, sinus infections, or bronchitis. Grade 1 and 2 nonhematologic or noninfectious toxicities were more common and included fatigue (92% of patients), diarrhea (55%), constipation (55%), rash (48%), and/or pruritus (43%). Grade 1 or 2 tumor flare reactions occurred in 31 (52%) patients, but these were generally mild and tolerated without further therapy (18 patients) or treated with short administration of nonsteroidal anti-inflammatory drugs (5 patients), steroids (9 patients), or dose adjustment of lenalidomide (10 patients). Almost all tumor flare reactions occurred within the first 3 cycles of therapy, with the majority occurring in the cycle. There were no grade 3 or 4 episodes of tumor flare or any tumor lysis in this study.

Serum Ig levels were measured at baseline and during treatment in the 34 patients who completed at least 15 cycles of therapy; 33 of these patients achieved an objective response. An increase in Ig levels across all Ig classes was noted. The rise in IgG and IgA was most pronounced between 3 and 9 cycles of therapy, whereas the rise in IgM occurred by the third cycle of therapy. Sixteen patients had decreased IgG levels (< 700 mg/dL) before therapy. In 8 patients (50%), IgG levels normalized after 15 cycles of therapy, and another 3 patients (19%) demonstrated an increase in IgG of greater than 50% from baseline. The rise in serum Ig levels was durable through therapy.

In the majority of patients, the number of total circulating lymphocytes decreased significantly during the first 3 cycles, which was sustained for the duration of therapy. The absolute number of CD3+ T cells was elevated in the majority of patients before start of therapy and decreased during therapy, 27 of 34 patients (79%) attained normal absolute CD3+ T-cell counts after 15 cycles of therapy. For these patients, T-cell numbers and the proportion of CD4 to CD8 lymphocytes remained within normal limits during treatment. There was no statistically significant association between severe infections and absolute T- or B-cell numbers or subsets in the periphery or in bone marrow before therapy.

CCL4 are chemokines secreted by CLL cells in the lymph node microenvironment in response to B-cell receptor (BCR) activation and can be detected in patient's plasma, where their concentrations predict for disease progression and time to first treatment. There was no correlation between pretreatment CCL3 or CCL4 levels and likelihood of response. Although no significant difference was observed in CCL3 and CCL4 levels after 3 cycles of therapy between responders (PR or CR) and nonresponders, after 9 cycles of therapy responders had significantly lower levels of CCL3 or CCL4 relative to pretreatment.

In this study, median PFS has not been reached after 30 months of follow-up. This duration of response compares favorably with the results of studies of chlorambucil, fludarabine, or alemtuzumab monotherapy that have generally been associated with median PFS of < 2 years. The ORR rate of 65% is similar to published results for monotherapy in elderly untreated patients with CLL, and the 2-year OS rate of 88% is promising in this older patient group. This is not a comparative study; therefore, these results require confirmation with larger phase 3 trials.

Overall, lenalidomide was well tolerated with neutropenia as the most common associated toxicity occurring in 34% of the cycles. Patients with neutropenia had doses withheld and/or reduced; therefore, the rate of neutropenia may have impacted on the exposure to lenalidomide and consequent efficacy. Although the rate of neutropenia was high, neutrophil recovery generally occurred spontaneously after withdrawal of therapy for 7-10 days and the overall rate of febrile neutropenic events was low. The rate of grade 3 or 4 infection was low and decreased in patients who continued therapy.

Prior studies of lenalidomide have reported frequent tumor flare reactions and severe tumor lysis syndrome in patients with CLL. Patients in this study did not experience any severe tumor flare or tumor lysis on this dose regimen. Grade 1 or 2 tumor flare was common and either resolved spontaneously or responded well to simple measures, such as nonsteroidal anti-inflammatory drugs, dose reduction of lenalidomide, or corticosteroids in a minority of patients. The low incidence of severe tumor flare that observed is probably related to the low starting dose of lenalidomide and gradual dose escalation. The development of tumor flare was associated with a higher likelihood of response as suggested by previously published findings in patients with CLL. This finding supports the recommendation to continue therapy with lenalidomide if tumor flare is not severe.

Lenalidomide exposure is associated with reversal of defective ability to form immune synapses between CLL cells and T cells and promotes costimulatory activation of B cells. In this study, an increase in Ig levels during treatment with lenalidomide occurred. This increased production of Igs is an interesting finding, which may be explained by enhanced B-cell costimulatory activity via activation of lymphocytes through phosphoinositide-3-kinase dependent up-regulation of CD154. In addition, a stimulatory effect of lenalidomide on T cells and NK cells has been demonstrated in vitro and in other hematologic malignancies. One study demonstrated up-regulation of costimulatory molecules, such as CD80 on CLL cells associated with T-cell activation after administration of lenalidomide in patients with CLL. The increase in CD80 expression correlated with tumor flare reaction, but the investigators were unable to correlate this with tumor response. NK-cell activation has also been demonstrated in lymphoproliferative disorders and myeloma. This, together with the dynamic changes noted in the repertoire of functional T cells in a subset of patients enrolled in this study, supports the immunomodulatory properties of this class of agents in CLL, similarly observed in other lymphoproliferative disorders after lenalidomide therapy.

Another interesting finding from this study is that responders exhibited a significant decrease in CCL3 and CCL4 levels during lenalidomide therapy compared with nonresponders. These chemokines are secreted by CLL cells after BCR signaling. It has been previously demonstrated that decreasing CCL3 and CLL4 levels are associated with response to therapy after inhibition of the BCR signaling pathway using the phosphoinositide 3′-kinase delta inhibitor CAL-101 or the Bruton tyrosine kinase inhibitor PCI-32765. The increase in CCL3 and CCL4 levels in nonresponders may represent continued activation of CLL cells via BCR signaling pathways, other microenvironmental stimulating pathways, or because of an increased burden of CLL cells. These data should be confirmed by larger studies and suggest that further studies examining combinations of lenalidomide with agents targeting the BCR signaling pathways may be of interest.

This is the best evidence yet that Revlimid is going to be an important player in CLL treatment.


George said...

Still the phase 3 ORIGIN trial ( compares Lenalidomide with the Chlorambucil dose (0.8mg/kg D1+15) which is widely believed to be 10% less than the CLL4 dosing and has already compared unfavourably with Bendamustine. Isn't this unfair?

Terry Hamblin said...

In the bendamustine trial the chlorambucil dose was according to 'ideal weight' which is a surrogate for height. That was why it underdosed for chlorambucil and gave such poor response rates.

Anonymous said...

My experience with low-dose Revlimid (Lenalidomide) has been wholly consistent with your last few paragraphs. I've been taking one 5mg capsule every other day since 1 May, 2011.

Additionally, between the last two monthly CBCs, my WBC count dropped to within normal range. My absolute lymphocyte count was cut in half.

early 60s professional living in Jersey exurbia said...

I am in relspse mode with increasing WBc, decreasing Hgb and plt along with bulky lympmadenopaty, am starting a Phase II with Revlimid, a dose escalation trial with no placebo arm. Not the same as these patients as almost 62 and prior tx X 3, but hope for same response. Wish me luck@

Anonymous said...

Do you know why the Respect trial has been put on hold?

Terry Hamblin said...

I did. It was because of a severe side effect in another trial. I haven't had an update.