Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma, including Chronic Lymphocytic Leukemia, and Acute Myeloid Leukemia in the Non-Hematopoietic Stem-Cell Transplant Setting
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/7:2013
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Monoclonal antibodies targeted to cancer-associated antigens have been approved by the U.S. Food and Drug Administration (FDA) for various uses in oncology. In some cases, these agents are used in settings outside of the FDA-approved label, i.e., off-label use.
Rituximab (Rituxan®) is a chimeric murine/human monoclonal antibody directed against the surface antigen CD20, which is expressed on all normal B lymphocytes and more than 90% of B-cell non-Hodgkin lymphomas (NHL). Rituximab induces lysis of B cells (normal and malignant) that express CD20 and also sensitizes B cells to the cytotoxic effect of chemotherapy.
Ofatumumab (Arzerra®) is also a monoclonal antibody directed against CD20. It targets an epitope that differs from the binding location of rituximab. (1) Rituximab complement-dependent cytotoxicity is dependent on CD20 expression; chronic lymphocytic leukemia (CLL) cells underexpress CD20, whereas ofatumumab does not appear to be similarly dependent on receptor intensity.
Alemtuzumab (Campath®) is a recombinant, humanized, monoclonal antibody directed against the cell surface protein CD52, which is expressed on most normal and malignant B and T lymphocytes but not on hematopoietic stem cells. Therefore, the antibody has the potential for broad application in treating B- and T-cell malignancies. Its mechanism of action appears to involve complement-mediated cell lysis, antibody-dependent cellular toxicity, and the induction of apoptosis.
Gemtuzumab (Mylotarg®) is a recombinant, humanized monoclonal antibody directed against the CD33 antigen, which is expressed on the surface of leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML) and by normal cells committed to the myeloid lineage, but not by pluripotent hematopoietic stem cells. Binding of the anti-CD33 antibody with the CD33 antigen results in formation of a complex that is internalized and eventually leads to DNA double-strand breaks and cell death.
This policy considers labeled and off-labeled indications for the uses of rituximab, ofatumumab, alemtuzumab, and gemtuzumab in NHL and AML in the non-hematopoietic stem-cell transplant setting.
On January 28, 2011, the U.S. Food and Drug Administration (FDA) approved a new expanded indication for rituximab for previously untreated follicular CD20-positive, B-cell NHL in combination with first-line chemotherapy and in patients achieving a complete (CR) or partial response (PR) to Rituxan® in combination with chemotherapy, as single-agent maintenance therapy.
On October 26, 2009, the U.S. Food and Drug Administration granted accelerated approval to ofatumumab (Arzerra®, GlaxoSmithKline) for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.
In September 2007, the FDA expanded the approved labeling for alemtuzumab to include its use in previously untreated patients with B-CLL (previous label approved only for treatment of B-CLL in treatment-experienced patients, specifically those who had been treated with an alkylating agent and whose disease was not adequately responding to fludarabine therapy). Labeling indications for alemtuzumab are as monotherapy for the treatment of CLL.
On June 21, 2010, in agreement with the U.S. Food and Drug Administration (FDA), the commercial marketing of Mylotarg® was voluntarily discontinued due to a lack of evidence to confirm clinical benefit for gemtuzumab as part of induction or maintenance therapy of AML. In addition, there were safety concerns, including a relatively high rate of fatal induction phase toxicities and higher than expected incidence of veno-occlusive disease. The withdrawal was based on the failure of a postapproval trial to confirm clinical benefit for gemtuzumab (trial S0106 conducted by the Southwest Oncology Group). Patients who are currently receiving gemtuzumab may complete their planned course of therapy; however, the drug will not be commercially available to new patients.
Rituximab (Rituxan®) may be considered medically necessary to treat patients with B-cell non-Hodgkin lymphoma (NHL) in any of the following clinical situations:
- for follicular lymphoma:
- as first-line therapy (as combination therapy or as monotherapy)
- as second or subsequent therapy (as combination therapy or as monotherapy)
- as single-agent maintenance therapy (first- or second-line) in patients who achieve a complete or partial response to Rituxan in combination with chemotherapy
- when used with CHOP or other anthracycline-based chemotherapy as first-line treatment for patients with diffuse large B-cell lymphoma (DLBCL)
- for recurrent, aggressive CD20-positive NHL
- for previously untreated or relapsed/refractory mantle cell lymphoma
- as combination therapy in previously untreated and previously treated B-cell chronic lymphocytic leukemia (B-CLL).
(See Policy Guidelines for FDA-approved indications for rituximab.)
Ofatumumab (Arzerra®) may be considered medically necessary for the treatment of CLL that is refractory to fludarabine and alemtuzumab.*
Ofatumumab (Arzerra®) is considered investigational in previously untreated CLL or as maintenance therapy in patients with CLL.
Ofatumumab (Arzerra®) is considered investigational for the treatment of malignancies other than B-cell CLL.
Alemtuzumab (Campath®) may be considered medically necessary as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL)* in patients with a chromosome deletion of 17p [del (17p)] or in patients not suitable for treatment with fludarabine.
Alemtuzumab (Campath®) is considered investigational for the treatment of malignancies other than B-cell CLL.
Gemtuzumab ozogamicin (Mylotarg®) may be considered medically necessary for the treatment of patients with CD33-positive acute myeloid leukemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Note that in June 2010, Pfizer, Inc. announced the voluntary withdrawal of Mylotarg® (gemtuzumab ozogamicin) from the U.S. market. Patients who are currently receiving the drug may continue their planned course of therapy; however, Mylotarg® will not be commercially available to new patients.
Gemtuzumab ozogamicin (Mylotarg®) is considered investigational for:
- treatment of patients with AML and who are younger than 60 years of age
- treatment of newly diagnosed AML
- treatment of second or subsequent relapse of AML
- use in combination with cytotoxic chemotherapy
*Indicates an indication approved by the U.S. Food and Drug Administration
Please refer to MP 5.01.01 for general guidelines for review of oncologic drugs.
Rituximab is approved by the FDA for the following indications:
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy.
- Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy.
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens.
- In combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.
Treatment of B-CLL with monoclonal antibody therapy is used in patients with non-localized disease (i.e., Ann Arbor, stage II-IV).
BlueCard/National Account Issues
State or federal mandates regarding off-label uses of drugs approved by the FDA may supersede this policy. Off-label uses for rituximab (Rituxan®) and alemtuzumab (Campath®) are from the American Hospital Formulary Service (AHFS) Drug Information. There are no off-label uses currently listed in the AHFS Drug Information for gemtuzumab ozogamicin (Mylotarg®).
The original policy was based on 2 TEC Assessments from 2001 and 2002. (2) (3)
The 2001 TEC Assessment addressed the off-label uses of the monoclonal antibodies listed in this policy. The 2002 TEC Assessment specifically addressed the use of rituximab for the treatment of intermediate and aggressive B-cell non-Hodgkin lymphoma (NHL, primarily diffuse large B-cell lymphoma [DLBCL]). It was based on one randomized, controlled trial (RCT) (4) and 3 uncontrolled studies that supported the policy statement for this use. Subsequent to publication of the 2002 TEC Assessment, additional RCTs on the use of rituximab have been published.
First-line Treatment of Follicular Lymphoma (FL)
Several Phase III trials have evaluated the efficacy of rituximab in combination with various chemotherapy regimens as first-line therapy for indolent NHL/follicular lymphoma (FL). With the exception of one trial, the addition of rituximab in combination with several different chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone), and others, resulted in significantly greater complete remission (CR) (41–79% vs. 10–63%, respectively; p<0.005), and greater overall response rates (81–96% vs. 57–90%, respectively; p<0.05). (5) The addition of rituximab to first- or second-line therapy with different chemotherapy regimens has shown variable results in improvement of overall survival (OS) rates in Phase III trials. (5) However, a meta-analysis of OS data from 4 trials with a total of 1,015 patients with FL, showed significantly improved OS when rituximab was added to chemotherapy compared to chemotherapy alone (hazard ratio [HR]) favoring treatment with the addition of rituximab (HR: 0.57; 95% confidence interval [CI]: 0.43–0.77). (5)
Hiddemann and colleagues reported the results of front-line therapy in advanced-stage FL in 428 patients randomized to CHOP alone or rituximab plus CHOP (R-CHOP). (6) In the patients who received R-CHOP, there was a significantly prolonged time-to-treatment failure (p<0.001), a higher overall response rate (96% vs. 90%, respectively; p=0.011), and a prolonged duration of remission (p=0.001). Additional follow-up on a subset of the original study group (patients aged 60 years and older) showed a 4-year progression-free survival (PFS) advantage of R-CHOP over CHOP (62.2% vs. 27.9%, respectively; p<0.0001,) and 4-year OS (90% vs. 81%, respectively; p=0.039).
Marcus and colleagues randomly assigned previously untreated patients with advanced-stage FL to CVP (n=159) or rituximab plus CVP (R-CVP; n=162). (7) Overall response and CR rates were 81% and 41%, respectively in the R-CVP arm versus 57% and 10%, respectively in the CVP arm, (p<0.0001). After a median follow-up of 30 months, the patients who received R-CVP had a median time to progression of 32 months versus 15 for CVP only (p<0.0001). The median time-to-treatment failure was 27 months for R-CVP versus 7 months for CVP (p<0.0001). An update of the study with a median follow-up of 53 months (8) showed an improvement in OS in the R-CVP arm, with an estimated 4-year OS of 83% versus 77% in the CVP arm (p=0.029).
Although trials have shown improved outcomes combining rituximab with chemotherapy, the issue of which chemotherapy regimen to use as initial therapy for FL (e.g., CHOP versus CVP) is still being debated.
The efficacy of rituximab as monotherapy in patients with relapsed or refractory low-grade FL has been examined in noncomparative multicenter trials, (9-15) as summarized in a review article. (16) Most trials included patients with low-grade or FL, and the majority of patients had stage 3 or 4 disease. Where specified, the median duration of follow-up ranged from 173 days to 1.5 years. Across studies, baseline characteristics were median patient age 50-58 years, 34-63% of patients were male, and patients had received a median of 2 prior treatments (two studies), 3 (three studies) or 4 (one study). Number of patients ranged from 30 to 166 across studies. Overall response rates were 38-48% after 4 weeks of rituximab therapy and 57% after 8 weeks of therapy. Complete remission rates ranged from 3% to 17%. The median duration of response ranged from 5.9-17.8 months, and the median time to progression was 8.1-16.3 months, after 4 weeks’ therapy. Median duration of response and median time to progression had not yet been reached after a median 13.4 and 19.4 months’ follow-up in patients who received 8 weeks of rituximab therapy. (16)
Maintenance Therapy in Previously Untreated FL
Salles and colleagues report the results of a Phase 3 RCT (the PRIMA study) which was undertaken in 223 centers in 25 countries. (17) The study assessed the potential benefit of 2 years of rituximab maintenance therapy after first-line treatment in patients with FL needing systemic therapy. A total of 1,217 patients received 1 of 3 non-randomized induction regimens consisting of rituximab and chemotherapy; 1,019 patients had a partial response (PR) or complete response (CR) and were then randomly assigned to receive either 2 years of rituximab maintenance therapy (n=505) or observation (n=513). The primary endpoint was PFS. After a median follow-up of 36 months, PFS was 74.9% (95% CI: 70.9-78.9) in the rituximab maintenance group and 57.6% (53.2-62.0) in the observation group (HR: 0.55, 95% CI: 0.44-0.68; p<0.0001). Two years after randomization, 71.5% of patients in the rituximab maintenance group were in CR versus 52.2% in the observation group (p=0.0001). More patients who were in PR at the time of randomization converted to a CR after 2 years in the rituximab maintenance group (52%) than those in the observation group (30%); estimated difference 22.2%, 95% CI: 11.2-33.3; p=0.0001. There was a significant reduction in the risk of starting a new antilymphoma treatment or death or starting a new chemotherapy or death in the maintenance group. Grade 3 and 4 adverse events were recorded in 24% of patients in the rituximab maintenance group and 17% in the observation group, with infections being the most common adverse event. OS did not differ significantly between groups; however, the authors state that since longer follow-up will be needed to show any possible effect of rituximab maintenance on OS, they would continue to follow these patients. The authors conclude that 2 years of rituximab maintenance therapy significantly prolongs PFS, delays the time to the next antilymphoma treatment and next chemotherapy, and improves the quality of the response in patients with previously untreated follicular lymphoma that is responsive to first-line rituximab plus chemotherapy.
Maintenance Therapy in Relapsed FL
In 2006, van Oers and colleagues evaluated the role of rituximab in both induction and maintenance of relapsed/refractory FL. (18) They randomized 465 patients to induction with 6 cycles of CHOP versus R-CHOP, with a second randomization of patients in CR or PR to rituximab maintenance or observation. Induction therapy that included rituximab yielded statistically significant improvement in overall response (85.1% vs. 72.3%; p<0.001) and complete remission rates (29.5% vs. 15.6%; p<0.001), and median PFS from first randomization (33.1 months vs. 20.2 – all respectively; p<0.001). Rituximab maintenance resulted in a median PFS from second randomization of 51.5 months versus 14.9 months, respectively, with observation (HR: 0.40; p<0.001). Rituximab maintenance also improved OS from the second randomization with OS rates of 85% in the rituximab arm versus 77% with observation alone at 3 years (p=0.011). In 2010, van Oers and colleagues reported on the long-term outcomes of maintenance in this same patient population, with a median follow-up of 6 years. (19) Maintenance therapy with rituximab improved PFS compared with observation (median, 3.7 years versus 1.3 years, respectively; p<0.001; HR: 0.55), both after CHOP induction (p<0.001; HR: 0.37) and R-CHOP (p=0.003; HR: 0.69). The 5-year OS was 74% in the rituximab maintenance arm and 64% in the observation arm (p=0.07). Rituximab maintenance was associated with a significant increase in grade 3 and 4 infections (9.7% versus 2.4% respectively; p=0.01). The authors concluded that the use of rituximab maintenance therapy in relapsed/resistant FL led to superior PFS and that, although the improvement in OS did not reach statistical significance, this may have been due to an unbalanced use of rituximab in post-protocol salvage treatment (after disease progression, rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance).
Studies on Maintenance Therapy that Included Previously Untreated and Relapsed FL
In 2010, Martinelli and colleagues reported the long-term follow-up of a randomized clinical trial comparing induction therapy with single-agent rituximab alone with or without prolonged maintenance therapy with rituximab in patients with FL. (20) Patient population consisted of those who had received prior chemotherapy (n=138) and those who were chemotherapy naïve (n=64). All patients received single-agent rituximab and, if they did not progress, they were randomly assigned to no further treatment (observation arm) or 4 additional doses of rituximab given at 2-month intervals. Median follow-up was 9.5 years, with all living patients having been observed for at least 5 years. The median event-free survival (EFS) for the observation versus the maintenance group was 13 months versus 24 months, respectively (p<0.001). Of the previously untreated patients, at 8 years’ follow-up, 45% of those who had received rituximab maintenance treatment after responding to rituximab induction (n=38) were still without event, compared to 22% in the observation group. The authors concluded that single agent rituximab and prolonged maintenance therapy with rituximab could result in long-term remission, particularly in patients who had received no prior treatment and responded to rituximab induction.
In 2009, Vidal and colleagues performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of maintenance rituximab on the OS of patients with FL. (21) (The report did not include the above 2010 Martinelli et al. study). The largest study included in the systematic review is outlined in further detail under maintenance therapy in relapsed FL. (18) Five studies were included (total of 1,143 patients) that compared rituximab maintenance therapy with observation or treatment at relapse (no maintenance). One study included only patients with previously untreated FL, 3 included patients with relapsed FL, and one study included both previously untreated and relapsed FL. In 3 trials, patients were randomly assigned to a type of induction therapy and subsequently underwent a second randomization to maintenance therapy or observation. The other 2 trials consisted of patients treated with the same induction therapy who were then subsequently randomly assigned to maintenance therapy or observation. Data for 985 patients were available for the meta-analysis of OS. Patients with refractory or relapsed FL had a clear survival benefit with maintenance rituximab therapy compared to patients in the observation group (HR of death: 0.58; 95% CI: 0.42-0.79; 4 trials). Among patients who were previously untreated, the survival benefit was not statistically significant (HR of death: 0.68; 95% CI: 0.37-1.25; 2 trials). Grade 3 or 4 adverse effects were reported in 3 trials and were higher in the rituximab maintenance arm (risk ratio [RR]:1.52, 95% CI: 1.00-2.30).
DLBCL and Other Aggressive NHL
The use of rituximab with a CHOP or CHOP-like regimen has been found to be more effective than chemotherapy alone as first-line treatment in patients with advanced-stage DLBCL and mantle-cell lymphoma (MCL) in several Phase III trials.
In 2010, Coiffier and colleagues reported the long-term outcomes of a randomized study (LNH-98.5) involving 399 elderly patients (defined as aged 60–80 years) with previously untreated, diffuse, large B-cell lymphoma who were randomized to 8 cycles of classical CHOP or R-CHOP. (22) Median follow-up was 10 years. Ten-year PFS was 36.5% (95% CI: 29.7–43.3%) with R-CHOP compared with 20% (95% CI: 14.6–26.2%) with CHOP only. Median OS was 8.4 years (95% CI: 5.4-not reached) in the R-CHOP arm and 3.5 years (95% CI: 2.2-5.5) in the CHOP arm (p<0.0001).
In 2008, Pfreundschuh and colleagues reported the results of an RCT of 1,222 elderly (aged 61–80 years) patients with aggressive CD20+ NHL to 6 or 8 cycles of CHOP (at 2-week intervals, also known as CHOP-14), with or without rituximab, and showed a significant improvement in EFS, PFS, and OS in patients receiving R-CHOP versus CHOP. (23) Three-year OS was 67.7% (62.0–73.5) for 6 cycles of CHOP-14, 66.0% (60.1–71.9) for 8 cycles of CHOP-14, 78.1% (73.2–83.0) for 6 cycles of R-CHOP-14, and 72.5% (67.1–77.9) for 8 cycles of R-CHOP-14. OS improved only after 6 cycles of R-CHOP-14 (RR: 0.63 [0.46–0.85]; p=0.0031). The authors concluded that of the 4 regimens studied, 6 cycles of R-CHOP was the preferred treatment for elderly patients.
In 2006, Habermann and colleagues reported a 2-stage, randomized trial of 632 patients 60 years or older with untreated DLBCL. (24) Patients were randomized to CHOP or R-CHOP, and 415 responders underwent a second random assignment to maintenance with rituximab or observation. Three-year failure-free survival (FFS) was 53% for R-CHOP and 46% for CHOP induction (HR: 0.78; 95% CI: 0.61 to 0.99; p=0.04). Two-year FFS rate after the second randomization for maintenance was 76% versus 61% for rituximab maintenance versus observation (p=0.009). A significant difference in the effect of the maintenance therapy with rituximab was seen according to the type of induction received, with maintenance rituximab significantly prolonging FFS after CHOP (HR: 0.45; 95% CI: 0.29–0.71; p=0.0004) but not after R-CHOP (HR: 0.93; 95% CI: 0.53–1.66; p=0.81). A secondary analysis was performed to evaluate the effect of induction therapy without maintenance rituximab. R-CHOP alone showed a significant decrease in the risk of treatment failure compared with CHOP (HR: 0.64; 95% CI: 0.47–0.85; p=0.003), with an estimated 3-year FFS rate of 52% for R-CHOP and 39% for CHOP. Survival was also longer after R-CHOP induction alone, with an estimated 3-year OS rate of 67% for R-CHOP versus 58% for CHOP (HR: 0.72; 95% CI: 0.52–1.00; p=0.05).
Recent use of molecular profiling has shown greater survival advantages with rituximab in certain histologically indistinguishable but distinctly different molecular subtypes of DLBCL. (25) Future clinical trials may include molecular profiling to identify the most beneficial treatment combinations incorporating newer therapeutic agents such as rituximab. (25)
Mantle Cell Lymphoma (MCL)
A prospective Phase II trial involved 97 patients with newly diagnosed MCL who received rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) alternating with high-dose methotrexate-cytarabine. (26) Of 97 assessable patients, the response rate was 97% with a complete or unconfirmed complete response rate of 87%. At a median follow-up time of 40 months, the 3-year FFS was 64% and OS was 82%. Patients 65 years of age or younger had a 3-year FFS of 73%. Toxicity was significant with a shorter FFS in patients older than age 65 years. An update of this patient population, after a median follow-up of 4.8 years, reported 5-year FFS and OS rates of 48% and 65%, respectively. (27)
In 2005, Lenz and colleagues published the results of a prospective, randomized trial of 122 patients with previously untreated advanced stage MCL comparing CHOP chemotherapy alone versus R-CHOP. (28) R-CHOP was superior in terms of overall response rate (94% vs. 75%, respectively; p=0.0054), CR rate (34% vs. 7%, respectively; p=0.00024), and time-to-treatment failure (median 21 vs. 14 months, respectively; p=0.0131). However, no differences were observed in PFS or OS between the two groups.
In 2004, Forstpointner and colleagues published the results of a prospective, randomized, open-label multicenter Phase III trial comparing the use of fludarabine, cyclophosphamide, and mitoxantrone (FCM), with and without the addition of rituximab, in patients with relapsed and refractory follicular and MCL. (29) The number of patients with MCL was 52, and the group that received FCM plus rituximab (R-FCM) showed a superior overall response rate of 58% versus 46%, respectively (p=0.282). A significantly longer OS was observed in the R-FCM group, with the median OS not reached at 2 years, versus an estimated median OS for the FCM group of 11 months (p=0.0042). At 2 years, the estimated OS in the R-FCM arm was 65%, compared with 35% in the FCM arm.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a disease of the older population and tends to have a prolonged course. It is generally treated in a conservative fashion, and often treatment is initiated only when a patient becomes symptomatic as the disease progresses. Treatment of an individual patient may be variable and depend on age and other risk factors, including certain molecular abnormalities. As CLL is generally considered incurable, the aim of treatment often is to induce CR, including eliminating minimal residual disease in the bone marrow. Minimal residual disease is usually evaluated by sensitive testing methods, which include flow cytometry or polymerase chain reaction (PCR), with patients free of minimal residual disease following treatment having longer remission duration and survival. (30)
Current chemotherapy options for CLL include alkylating agents such as chlorambucil or cyclophosphamide (which when used as single agents have shown CR rates of less than 10%) and purine analogs such as fludarabine (with single-agent CR rates of 20%). The combination of an alkylating agent and fludarabine improves the CR to 40%. (31)
A 2012 Cochrane review compared the clinical benefits and harms of monoclonal anti-CD20 antibodies compared to no further treatment or to other anti-leukemic therapies in patients with CLL, irrespective of disease status. (32) Both pre-treated and chemotherapy-naïve patients were included, and all of the trials included in the review were randomized and open-label. Three RCTs (n=1,421) assessed the efficacy of rituximab plus chemotherapy compared to chemotherapy alone, and a meta-analysis found a statistically significant OS and PFS advantage for the patients who received rituximab. Although there were more grade 3 and 4 adverse events in the rituximab arm, it did not lead to a statistically significant difference regarding treatment-related mortality. Two RCTs (n=177) evaluated rituximab versus alemtuzumab; neither study reported PFS or OS. There was no statistically significant difference between arms regarding complete response rate or treatment-related mortality; however, more serious adverse events occurred in the alemtuzumab arm.
Previously Untreated CLL
In 2010, Hallek and colleagues reported the results of a randomized, open-label, multicenter Phase 3 trial (CLL8 trial). (33) Treatment-naïve patients with CLL were randomized to receive fludarabine and cyclophosphamide with (n=408) versus without (n=409) rituximab in 190 centers in 11 countries. At 3 years after randomization, 65% of patients in the chemoimmunotherapy group were free of progression versus 45% in the chemotherapy-only group (HR: 0.56 95% CI: 0.46-0.69; p<0.0001), and 87% were alive versus 83%, respectively (HR: 0.67 0.48-0.92; p=0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (34% versus 21%; p<0.0001) and leukopenia (24% versus 12%; p<0.0001); however, other side effects, including severe infections, were not increased. Treated-related deaths occurred in 2% versus 3% of patients in the chemoimmunotherapy and chemotherapy only groups, respectively. The authors concluded that the addition of rituximab improves PFS and OS in patients with previously untreated CLL.
In 2008, Tam and colleagues reported the results of a Phase II study of 300 patients with previously untreated CLL who received a combination of fludarabine, cyclophosphamide, and rituximab (FCR), with a median follow-up of 6 years. (34) Overall response rate was 95%, with a CR of 72%. Six-year OS was 77% and FFS was 51%. Compared to historical controls treated at the same institution with frontline fludarabine-based regimens, therapy with FCR was associated with a significantly superior OS (p<0.001); after adjusting for differences in pretreatment variables, FCR therapy emerged as the strongest independent predictor of survival (p<0.001, HR: 0.48). To date, the FCR regimen in this study has shown the highest CR rate, longest remission duration, and most favorable survival outcome for first-line therapy of CLL.
Byrd and colleagues performed a retrospective comparison of the outcomes of patients enrolled in a randomized Phase II study of 104 previously untreated CLL patients who received sequential or concurrent fludarabine plus rituximab therapy to patients with similar pretreatment characteristics treated on the fludarabine arm (n=178) of a randomized Phase III trial comparing fludarabine, chlorambucil, or both. (35) Results showed that patients who received fludarabine plus rituximab had a significantly better PFS and OS over the patients who received fludarabine alone. Two-year PFS probability was 0.67 (95% CI: 0.58–0.76) in patients who received fludarabine plus rituximab compared to 0.45 (95% CI: 0.37–0.52) for fludarabine alone (p<0.0001). Patients who received fludarabine plus rituximab had a 2-year OS probability of 0.93 (95% CI: 0.88–0.98) versus 0.81 (95% CI: 0.75–0.87) with fludarabine alone (p=0.003).
Relapsed or Refractory CLL
In 2010, the randomized, open-label multicenter Phase 3 REACH trial examined the efficacy of adding rituximab to fludarabine (F) and cyclophosphamide (C) in patients with relapsed or refractory CLL. (36) Patients were eligible if they had received 1 prior line of chemotherapy, were fludarabine sensitive, and had not received prior therapy with rituximab. Patients were randomized to receive FC plus rituximab (n=276) or FC only (n=276). The primary endpoint was PFS, with a median follow-up of 25 months. Median PFS was significantly prolonged in the FC plus rituximab group versus the FC only group (30.6 months versus 20.6 months, respectively; HR: 0.65; p<0.001). Also significantly higher in the FC plus rituximab group were the overall response and CR rates and the duration of overall response (HR: 0.69; 95% CI: 0.50-0.96). Median time to new treatment was also significantly longer in patients receiving rituximab (not reached versus 34.3 months; HR: 0.65; 95% CI: 0.49-0.86; p<0.01).
In 2011, Badoux and colleagues reported the final analysis of an open-label Phase 2 trial of 284 patients with relapsed CLL treated with FC and rituximab. (37) All of the patients included in the study had active, progressive CLL and included patients in second and subsequent relapse and those previously treated with rituximab or FC combination. Median patient age was 60 years and median number of prior treatments was 2 (range 1-10). The primary objective was to improve the CR rate compared with historic control patients treated with FC as salvage therapy (n=114). Secondary outcomes included OS and PFS, calculated from the first day of therapy. A total of 280 patients were evaluable for a response to FCR; 30% achieved CR, 14% achieved nodular partial remission (nPR), defined as patients who are otherwise in CR but have lymphoid nodules identified in bone marrow, and 30% achieved PR, for an overall response rate of 74%. When analyzed by prior therapy, patients with 3 or fewer prior therapies had significantly higher CR or nPR rates compared with those who received 4 or more prior regimens (52% vs. 4%, respectively; p<0.0001). The estimated median PFS was 20.9 months (95% CI: 18.8-27.6 months) for the entire cohort. The estimated median PFS for patients achieving CR was 60 months compared with 38 months for patients achieving nPR (p=0.076) and 15 months for those achieving PR (p<0.001). The estimated median OS for all patients was 46.7 months (95% CI: 41.2-53.4 months) and 100 months for patients who achieved CR or nPR. Compared with the historical cohort, patients receiving FCR had longer PFS compared to those receiving FC (21 months vs. 11 months, respectively; p<0.001) and longer OS (47 months vs. 21 months, respectively; p<0.001). A subgroup analysis showed that the following patients had superior outcomes with FCR: those with up to 3 prior treatments, fludarabine-sensitive patients regardless of prior rituximab exposure, and patients without chromosome 17 abnormalities.
National Comprehensive Cancer Network Guidelines
National Comprehensive Cancer Network (NCCN) guidelines (38) state that use of rituximab includes the following indications:
- FL (grade 1 or 2): as first-line therapy as chemoimmunotherapy with bendamustine or CVP or CHOP (category 1); with fludarabine-based therapy (category 2B); or as single agent therapy (category 2A)
- FL (grade 1 or 2): as first-line therapy as a single agent for elderly or infirm, if not able to tolerate above first-line therapy, (preferred) (category 2A) or with single agent alkylators (2A)
- FL (grade 1 or 2): as maintenance therapy, first and second line (category 1)
- FL: second-line and subsequent therapy: with fludarabine-based therapy [fludarabine, cyclophosphamide, mitoxantrone, rituximab] (category 1); radioimmunotherapy (category 1); chemoimmunotherapy as in first-line treatment;
- Extranodal marginal zone B-cell lymphoma
- First-line therapy in DLBCL in combination with various chemotherapy regimens
- DLBCL as second-line therapy (in patients who are not candidates for hematopoietic stem-cell transplant) in combination with chemotherapy or as monotherapy
- CLL: in patients without del (11q) or del (17p)
- First-line therapy: as single agent in frail patients with significant comorbidities (not able to tolerate purine analogs), in patients 70 years or older or younger patients with co-morbidities as single or combination therapy, and in patients younger than 70 years without significant comorbidities as combination therapy- (all category 2A)
- Relapsed/refractory: same as first-line therapy if long response (>3 years) until short response, and for short response (<2 years) in patients 70 years and older as single (category 2B) or combination (category 2A) and in patients younger than 70 years without significant comorbidities as combination therapy (category 2A)
- CLL: in patients with del (17p)
- As combination therapy for first-line and relapsed/refractory disease (category 2A)
- CLL: in patients with del (11q):
- First-line therapy age 70 years or older or younger patients with comorbidities as single agent or in combination (2A) and in patients age 70 years or less or older patients without significant comorbidities as combination therapy.
- CLL: in patients with del (11q):
- As therapy for relapsed/refractory disease: same as first-line therapy if long response until short response; as single agent or in combination if short response for age 70 or greater; as combination therapy if short response for age less than 70 years or in older patients without significant comorbidities.
- MCL as first- and second-line therapy in combination with chemotherapy (category 2A), and as maintenance therapy (category 1).
- As part of induction therapy and 2nd line therapy for Burkitt lymphoma
- In certain cases of lymphoblastic lymphoma, AIDS-related B-cell lymphoma, cutaneous B-cell lymphoma, post-transplant lymphoproliferative disorder and hairy cell leukemia.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®)
A search of the National Cancer Institute’s Physician Data Query (PDQ) database identified 7 Phase III trials investigating the use of rituximab in CLL, including first-line and maintenance therapy (NCT00275054, NCT00513747, NCT00564512, NCT00645606, NCT01118234, NCT00281918 and NCT00718549).
Fourteen Phase III trials are investigating the use of rituximab in indolent NHL including FL and mucosa-associated lymphatic tissue (MALT) lymphoma in previously untreated disease, the relapsed/refractory setting, as maintenance therapy and compared to radioimmunotherapy (NCT01200589, NCT00078598, NCT00115700, NCT00641095, NCT00004112, NCT00006721, NCT00075946, NCT00140582, NCT00006708, NCT00064116, NCT00003204, NCT00112931, NCT00210353 and MAYO-977802) and 6 in aggressive NHL including DLBCL and MCL (NCT00278421, NCT01287741, NCT209209, NCT00400478, NCT00028717, and NCT00641095).
A 2010 review article summarizes the clinical experience with ofatumumab. (1)
In 2008, in a Phase 1/2 open-label, dose-escalating trial, patients with relapsed or refractory CLL (n=33) were given weekly treatments of ofatumumab monotherapy. (39) Patients had received a median of 3 previous treatments (range, 1-9 treatments). The objective response rate with the highest dose of ofatumumab was 50%, with most responses sustained at week 19. The majority of patients who received the highest dose had a greater than 50% decrease in lymph node size, which was sustained through 15-27 weeks. The median time to next CLL therapy was 12 months, and the ofatumumab was well-tolerated. These initial, encouraging results with ofatumumab monotherapy in advanced CLL were further investigated in a multicenter study, (40) as outlined below.
In 2010, Wierda and colleagues reported a planned interim analysis of patients treated with ofatumumab monotherapy who had either fludarabine or alemtuzumab refractory (FA-ref) CLL or were ineligible for alemtuzumab treatment due to fludarabine-refractory CLL with bulky (>5 cm) lymphadenopathy (BF-ref). (40) (These groups have poor outcomes with available salvage regimens. For comparison, the authors cite a case series of 99 patients with FA-ref CLL [n=58] or BF-ref [n=41] who were treated with a variety of salvage regimens, including monoclonal antibodies, single agent or combination chemotherapy, or allogeneic hematopoietic stem-cell transplantation. Patients had low response rates [23% overall], short time-to-treatment failure [median, 2-3 months], and an OS of 9 months). (41) The overall response rates (primary endpoint) were 58% (99% CI: 40-74%) and 47% (99% CI: 32-62%) in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. In the FA-ref group, median PFS and OS were 5.7 months (95% CI: 4.5-8.0) and 13.7 months (95% CI: 9.4-not yet reached), respectively, and 5.9 months (95% CI: 4.9-6.4) and 15.4 months (95% CI: 10.2-20.2) in the BF-ref group, respectively. Adverse events were most commonly seen during treatment and included infusion reactions and infections and were primarily grade 1 or 2 events.
Czuczman and colleagues reported on the use of ofatumumab as monotherapy in rituximab-refractory FL. (42) The median age of these patients was 61 years-old, and 47% had high-risk Follicular Lymphoma International Prognostic Index scores. Sixty-five percent were chemotherapy-refractory, and the median number of prior therapies was 4. Overall response rate was 13% and 10% for 2 different doses, respectively. Among 27 patients refractory to rituximab monotherapy, overall response rate was 22%. Median PFS was 5.8 months. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. The authors concluded that ofatumumab was well tolerated and modestly active in this heavily pre-treated, rituximab-refractory patient population.
National Comprehensive Cancer Network Guidelines
National Comprehensive Cancer Network (NCCN) guidelines (38) state that use of ofatumumab includes the following indications:
- In patients with CLL relapsed/refractory without del (11q) or del (17p) who have a short response to initial therapy (<2 years): for age ≥70 years, age <70 years, or older patients without significant co-morbidities (category 2A)
- In patients with CLL relapsed/refractory with del (17p) with lymph nodes <5 cm- (category 2A)
- In patients with CLL relapsed/refractory with del (11q), who have a short response to initial therapy (<2 years): for age ≥70 years, for age <70 years, or for older patients without significant co-morbidities (category 2A)
National Cancer Institute (NCI) Clinical Trial Database (PDQ®)
A search of the National Cancer Institute’s Physician Data Query (PDQ) database identified 8 Phase III trials investigating the use of ofatumumab in the treatment of CLL, in patients who are previously untreated, as maintenance therapy and in the relapsed/refractory setting as monotherapy or combination therapy. (NCT00748189, NCT00824265, NCT01039376, NCT01077518, NCT01200589, NCT01313689, NCT00349349)
Patients with CLL and the presence of del (17p) (the location of the p53 gene) are generally resistant to chlorambucil, fludarabine, and rituximab, and patients with this mutation show disease progression and poor survival outcomes. Whereas median OS for patients with CLL is approximately 10 years, patients with del (17p) have a median survival of 32 months. (43) Alemtuzumab has been investigated as a treatment option in these patients.
Alemtuzumab was initially approved in 2001 after the results of the pivotal CAM 211 Phase 3 study, in which 93 patients with relapsed or refractory CLL who had failed prior therapy with fludarabine or an alkylating agent, were treated with alemtuzumab and significant responses were observed. (44) The overall response rate was 33% (2% CR and 31% PR). Median time to progression was 4.7 months and median OS was 16 months (95% CI: 11.8-21.9) and 32 months for responders.
In a Phase 2 study, 103 patients with fludarabine-refractory CLL received at least 1 dose of alemtuzumab, and achieved an overall response rate of 34% (4% CR and 30% PR). (45) Median PFS was 7.7 months and median OS, 19.1 months.
Lozanski and colleagues reported the effectiveness of alemtuzumab in 36 patients with fludarabine-refractory CLL, 15 (42%) of whom had p53 mutations or deletions. (46) They observed a clinical response (complete or partial response) in 6 of 15 (40%) patients with this mutation versus a response rate of only 19% in patients without.
In 2007, Hillmen and colleagues reported the results of the CAM307 trial, which randomized 297 patients with previously untreated CLL to either alemtuzumab (n=149; median age 59 years; range, 35–86 years) or chlorambucil (n=148; median age 60 years; range, 36–83 years) as first-line treatment. (47) Overall median PFS was 14.6 months (95% CI: 12.3–21.7 months) for patients in the alemtuzumab arm versus 11.7 months (95% CI: 9.9–13.2 months) in the chlorambucil arm (p=0.0001). Overall and complete response rates were better in the alemtuzumab arm, 83.2% versus 55.4% (p<0.0001) and 24.2% versus 2.0% (p<0.0001), respectively. After a median follow-up of 24.6 months, 84% of the patients in each arm were alive. Based on this study, the U.S. Food and Drug Administration (FDA) granted regular approval and expanded labeling for alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia (B-CLL). Commentary on the Hillmen et al. trial raised several points: during the study’s enrollment, work by Rai et al. established an advantage of using fludarabine over chlorambucil as the basis of CLL therapy, with a shift toward the use of fludarabine-based combination therapy in young patients. (48) In addition, the PFS shown in the CAM307 study was inferior to that observed in many randomized and Phase III studies published in the last decade, and the CAM307 trial did not provide OS data past the trial follow-up of 24.6 months.
In a single-arm study of 91 previously treated CLL patients, alemtuzumab led to eradication of minimal residual disease (MRD) in 20% of patients. (49) Patients achieving an MRD-negative complete response had longer treatment-free survival (not reached) than MRD-positive complete response patients (20 months) and MRD-positive partial response patients (13 months; p<0.0001). Five-year OS was 84% for the MRD-negative patients, compared to approximately 10% of fludarabine-refractory patients treated with conventional salvage therapy expected to survive 5 years. The authors conclude that MRD-negative remissions can be attained with alemtuzumab in patients with relapsed/refractory CLL, leading to improvement in OS and treatment-free survival.
A review article by Dearden summarizes recent studies with single-agent alemtuzumab in the management of T-cell leukemia/lymphoma. (50) One study of 39 patients with relapsed/refractory T-prolymphocytic leukemia (T-PLL) showed a 60% CR rate in patients treated with alemtuzumab, compared to a 9% CR rate with the purine nucleoside analog 2-deoxycoformycin (DCF). Preliminary results in a study of 11 patients with treatment-naive T-PLL showed a CR rate of 100%. Despite these reported improved response rates, studies of the use of alemtuzumab in these disorders have been small and have not shown OS benefit. Further, some have been associated with significant toxicity and therefore require further investigation.
As combination chemoimmunotherapy
Elter and colleagues reported the results of a Phase 3, open-label, randomized trial in which fludarabine plus alemtuzumab was compared to fludarabine alone in patients with previously treated (relapsed or refractory) CLL. (51) The primary endpoint was PFS. Fludarabine plus alemtuzumab (n=168) resulted in better PFS than fludarabine monotherapy (n=167) (median 23.7 months [95% CI: 19.2-28.4] vs. 16.5 months [12.5-21.2]; hazard ratio (HR): 0.61 [95% CI: 0.47-0.80]; p=0.0003) and OS (median not reached vs. 52.9 months [40.9-not reached]; 0.65 [0.45-0.94]; p=0.021). Deaths due to adverse events were similar between the two groups.
Badoux and colleagues reported outcomes for 80 patients with relapsed or refractory CLL who were enrolled in a Phase 2 study and received alemtuzumab in addition to cyclophosphamide, fludarabine and rituximab. (52) Patients were considered to be high-risk (e.g., refractory to fludarabine or high-risk cytogenetic abnormalities). Compared to historic controls, there was no significant improvement in PFS, and OS appeared worse.
Parikh and colleagues reported the results of a Phase 2 trial for 60 high-risk, previously untreated patients with CLL treated with fludarabine, cyclophosphamide, alemtuzumab and rituximab. (53) High risk was defined as serum β-2 microglobulin greater than or equal to 4 mg/L. Response rates and survival were comparable to historic high-risk patients treated with fludarabine, cyclophosphamide, and rituximab.
National Comprehensive Cancer Network (NCCN) Guidelines
NCCN guidelines (38) state that alemtuzumab is indicated (all category 2A):
- As first-line treatment of CLL in patients without del (11q) or del (17p), as monotherapy in patients 70 years of age or older.
- In the treatment of relapsed/refractory CLL in patients without del (11q) or (17p), in patients with a short response to first-line therapy (<2 years) and age ≥70 with or without rituximab, and in patients with a short response to first-line therapy (<2 years) and age <70 or older patients without significant co-morbidities with fludarabine or with or without rituximab.
- In patients with CLL and del (17p) as first-line therapy (monotherapy or with rituximab) and for relapsed/refractory disease as combination therapy with chemotherapy, or with or without rituximab.
- In patients with CLL and del (11q) as first-line therapy in patients age ≥70 years or younger patients with co-morbidities as monotherapy.
- In patients with CLL and del (11q) as relapsed/refractory therapy in patients with a short response (<2 years) to first-line therapy for age ≥70 years with or without rituximab and for patients with a short response (<2 years) for age <70 years or older patients without significant co-morbidities with fludarabine or with or without rituximab.
- for noncutaneous, peripheral T-cell lymphomas as second-line therapy in non-candidates for hematopoietic stem-cell transplantation.
- for cutaneous T-cell lymphomas (i.e., mycosis fungoides/Sezary syndrome) for refractory or progressive disease, stage 3 or 4 (Sezary syndrome).
- for T-cell prolymphocytic leukemia as primary treatment for symptomatic disease as monotherapy or in combination.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®)
A search of the National Cancer Institute’s PDQ database identified 3 Phase III trials investigating the use of alemtuzumab in B-CLL, including as front-line therapy and in the relapsed/refractory setting. (NCT00046683, NCT00086580, NCT00564512)
One Phase III trial is ongoing investigating the value of alemtuzumab in previously untreated T-cell malignancies in the non-hematopoietic stem-cell transplant setting. NCT00725231 is an open-label interventional trial that will randomize elderly patients with previously untreated peripheral T-cell lymphoma to CHOP-14 with or without alemtuzumab. Estimated enrollment is 274, with an estimated study completion date of March 2014.
Gemtuzumab Ozogamicin (Mylotarg®)
FDA approval of gemtuzumab for patients with CD33-positive AML in first relapse who are aged 60 years or older and not candidates for other cytotoxic chemotherapies was based on an evaluation of 277 patients in 3 single-arm, open-label, Phase II studies. (54) In 2 of the studies, patients were 18 years of age or older with a first remission duration of at least 6 months, and in the third study, only patients 60 years of age or older and in a first remission lasting at least 3 months were enrolled. Of the 3 studies combined, 157 patients were 60 years of age or older. The primary endpoint of the 3 studies was CR, and secondarily, CR that includes platelet transfusion independence (CRp). For the 3 pooled studies, in patients older than 60 years of age, the CR was 12%, and CRp was 12% (CR and CRp in patients younger than age 60 years were 13% and 14%, respectively). For patients who were younger than 60 years of age versus all 277 patients combined, the overall response rates were 28% and 26%, respectively. For patients 60 years of age or older, overall response rate was 24%. For those patients who completed the treatment period, median OS was 12.2 months for patients with CR and 12.9 months for patients in the CRp group (vs. 4.2 months for patients who did not enter remission; p<0.001). The median OS for patients younger than age 60 years in the CR and CRp groups was 17.2 and 18.4 months, respectively. For patients 60 years of age or older, OS was 11.7; it was 11.4 months for those in the CR and CRp groups, respectively.
Lowenberg and colleagues reported the results of a multicenter Phase III study randomizing patients older than 60 years of age with acute myeloid leukemia (AML), or refractory anemia with excess blasts to 3 cycles of gemtuzumab or no post-remission therapy (control) after first CR was attained after intensive induction chemotherapy. (55) The 2 treatment groups (113 received gemtuzumab and 119 were control patients) were comparable regarding age (60–78 years, median: 67 years), performance status, and genetics. Sixty-five of the 113 patients completed the 3 cycles of gemtuzumab (a total of 110 of 113 received at least 1 cycle). The authors found no significant differences between treatment groups with regard to relapse probabilities, nonrelapse mortality, disease-free survival (DFS) or OS, and concluded that post-remission treatment with gemtuzumab in older AML patients does not provide clinical benefit.
Burnett and colleagues reported on the outcomes of an open-label trial of 1,113 patients, predominantly younger than 60 years of age, with previously untreated AML. (56) Patients were randomized to the addition of gemtuzumab to induction and/or consolidation chemotherapy. The primary endpoints of the trial were response rate and survival. The addition of gemtuzumab was well-tolerated with no significant increase in toxicity. Overall, there was no difference with the addition of gemtuzumab in response or survival in either induction or consolidation. A predefined analysis by cytogenetics showed highly significant interaction with induction gemtuzumab (p=0.001) with significant survival benefit for patients with favorable cytogenetics, no benefit for patients with poor-risk disease, and a trend for benefit in intermediate-risk patients. The authors concluded that a substantial proportion of younger patients with AML have improved survival with the addition of gemtuzumab to induction chemotherapy with little additional toxicity.
NCCN guidelines (57) state that gemtuzumab is no longer commercially available in the U.S. after the U.S. Food and Drug Administration (FDA) withdrew its prior approval for the drug for the treatment of older patients with relapsed AML, but that trials suggest that the addition of gemtuzumab to standard induction regimens reduced the risk of relapse and improved OS outcomes in older patients with previously untreated AML. NCCN makes no recommendations on the use of gemtuzumab.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®)
A search of the National Cancer Institute’s Physician Data Query database identified 11 Phase II/III and Phase III trials to assess chemotherapy with or without gemtuzumab. Studies include patients in various age groups (including those younger than 60 years of age) and with relapsed and previously untreated AML: NCT00454480, NCT00085709, NCT00372593, NCT00492856, NCT00860639, NCT00893399, NCT00121303, NCT00927498, NCT00052299, NCT00091234 and NCT00049517.
Physician Specialty Society and Academic Medical Center Input
In response to requests, input was received from a physician specialty society and 2 academic medical centers while this policy was under review in 2009, for a total of 4 reviews. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Two reviewers commented on 3 monoclonal antibodies addressed in the policy, and 2 only commented on gemtuzumab. (This policy was sent out for vetting before the addition of ofatumumab to the policy).
Rituximab: The 2 reviewers were split on the use of rituximab 1) with CHOP as first-line therapy for FL, 2) as first- and second-line therapy of MCL, and 3) in the treatment of relapsed or refractory CLL.
Alemtuzumab: Both reviewers agree with the policy statements and state that alemtuzumab is most appropriately used in patients with a chromosome 17p deletion, or any patient not suitable for treatment with fludarabine (1 reviewer).
Gemtuzumab: Three of the 4 reviewers agreed on the statement of medical necessity; 3 of the 4 reviewers disagreed with the investigational statement, and all 3 based this on the results of a recent, large Phase III study using gemtuzumab in patients predominantly younger than age 60 years; at the time of their review, this study was available in abstract form; it has since been published in its entirety. (51)
Randomized studies have shown that the addition of rituximab to front-line chemotherapy has resulted in improved response rates and survival in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL).
The efficacy of rituximab as monotherapy in relapsed/refractory FL has been shown in noncomparative, multicenter trials.
Randomized trials have shown improved progression-free survival (PFS) and overall survival (OS) with the use of rituximab as maintenance therapy, both in patients with previously untreated and previously treated FL.
Randomized studies have shown that the addition of rituximab to chemotherapy has resulted in improved response rates and time-to-treatment failure in newly diagnosed mantle-cell lymphoma (MCL) and improved OS in relapsed or refractory disease.
Randomized studies have shown improved PFS and OS with the addition of rituximab to chemotherapy in previously untreated chronic lymphocytic leukemia (CLL). One randomized study showed prolonged PFS in relapsed/refractory CLL, and a Phase 2 open-label trial showed improved PFS and OS.
Compared to historical controls, ofatumumab has shown improved OS rates in patients with CLL that is refractory to fludarabine and alemtuzumab or who are ineligible for alemtuzumab due to bulky disease.
More data are needed on the use of ofatumumab in patients with rituximab-refractory FL.
Single-agent alemtuzumab has shown efficacy in patients with CLL, particularly in the subgroup of patients with high-risk cytogenetic markers (e.g., del(17p13.1)).
More data are needed on the use of alemtuzumab as part of combination chemoimmunotherapy in the treatment of previously untreated and relapsed/refractory CLL.
Small studies have shown some activity with alemtuzumab in relapsed/refractory cutaneous and peripheral T-cell lymphomas but have been associated with significant toxicity, and not shown survival benefit.
- Gemtuzumab: On June 21, 2010, in agreement with the U.S. Food and Drug Administration (FDA), the commercial marketing of Mylotarg® was voluntarily discontinued due to a lack of evidence to confirm clinical benefit for gemtuzumab as part of induction or maintenance therapy of AML. Patients who are currently receiving gemtuzumab may complete their planned course of therapy; however, the drug will not be commercially available to new patients.
- O'Brien S, Osterborg A. Ofatumumab: a new CD20 monoclonal antibody therapy for B-cell chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2010; 10(5):361-8.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Off-label uses of monoclonal antibodies for treatment of B-cell lymphoid or myeloid malignancies. TEC Assessments 2001; Volume 16, tab 7.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Rituximab for treatment of intermediate or aggressive B-cell non-Hodgkin’s lymphoma. TEC Assessments 2002; Volume 17, Tab 3.
- Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346(4):235-42.
- Cvetkovic RS, Perry CM. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs 2006; 66(6):791-820.
- Hiddemann W, Kneba M, Dreyling M et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106(12):3725-32.
- Marcus R, Imrie K, Belch A et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105(4):1417-23.
- Turturro F. Update on front-line therapy for follicular lymphoma: chemo-immunotherapy with rituximab and survival. Expert Rev Anticancer Ther 2007; 7(7):959-65.
- Feuring-Buske M, Kneba M, Unterhalt M et al. IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group. Ann Hematol 2000; 79(9):493-500.
- Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997; 90(6):2188-95.
- Davis TA, Grillo-Lopez AJ, White CA et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000; 18(17):3135-43.
- Davis TA, White CA, Grillo-Lopez AJ et al. Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 1999; 17(6):1851-7.
- Piro LD, White CA, Grillo-Lopez AJ et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 1999; 10(6):655-61.
- McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16(8):2825-33.
- Foran JM, Gupta RK, Cunningham D et al. A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 2000; 109(1):81-8.
- Keating GM. Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma. Drugs 2010; 70(11):1445-76.
- Salles G, Seymour JF, Offner F et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377(9759):42-51.
- van Oers MH, Klasa R, Marcus RE et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108(10):3295-301.
- van Oers MH, Van Glabbeke M, Giurgea L et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010; 28(17):2853-8.
- Martinelli G, Schmitz SF, Utiger U et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28(29):4480-4.
- Vidal L, Gafter-Gvili A, Leibovici L et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009; 101(4):248-55.
- Coiffier B, Thieblemont C, Van Den Neste E et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010; 116(12):2040-5.
- Pfreundschuh M, Schubert J, Ziepert M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9(2):105-16.
- Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24(19):3121-7.
- Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362(15):1417-29.
- Romaguera JE, Fayad L, Rodriguez MA et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 2005; 23(28):7013-23.
- Fayad L, Thomas D, Romaguera J. Update of the M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma 2007; 8 Suppl 2:S57-62.
- Lenz G, Dreyling M, Hoster E et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; 23(9):1984-92.
- Forstpointner R, Dreyling M, Repp R et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004; 104(10):3064-71.
- Wierda WG KM, O’Brien S, . In: DeVita VT Jr. LT, Rosenberg SA, ed. Cancer: Principles and Practice of Oncology . 8th ed. Philadelphia: Lippincott Williams and Wilkins:2278-92.
- Boyd K, Dearden CE. Alemtuzumab in the treatment of chronic lymphocytic lymphoma. Expert Rev Anticancer Ther 2008; 8(4):525-33.
- Bauer K, Rancea M, Roloff V et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2012; 11:CD008079.
- Hallek M, Fischer K, Fingerle-Rowson G et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376(9747):1164-74.
- Tam CS, O'Brien S, Wierda W et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112(4):975-80.
- Byrd JC, Rai K, Peterson BL et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005; 105(1):49-53.
- Robak T, Dmoszynska A, Solal-Celigny P et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28(10):1756-65.
- Badoux XC, Keating MJ, Wang X et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011; 117(11):3016-24.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphoma. 2.2012. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Last accessed April, 2012.
- Coiffier B, Lepretre S, Pedersen LM et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008; 111(3):1094-100.
- Wierda WG, Kipps TJ, Mayer J et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010; 28(10):1749-55.
- Tam CS, O'Brien S, Lerner S et al. The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma 2007; 48(10):1931-9.
- Czuczman MS, Fayad L, Delwail V et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 2012; 119(16):3698-704.
- Dohner H, Stilgenbauer S, Benner A et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343(26):1910-6.
- Keating MJ, Flinn I, Jain V et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99(10):3554-61.
- Stilgenbauer S, Zenz T, Winkler D et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009; 27(24):3994-4001.
- Lozanski G, Heerema NA, Flinn IW et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103(9):3278-81.
- Hillmen P, Skotnicki AB, Robak T et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25(35):5616-23.
- Flynn JM, Byrd JC. Have we forgotten the purpose of phase III studies? J Clin Oncol 2007; 25(35):5553-5.
- Moreton P, Kennedy B, Lucas G et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23(13):2971-9.
- Dearden C. The role of alemtuzumab in the management of T-cell malignancies. Semin Oncol 2006; 33(2 Suppl 5):S44-52.
- Elter T, Gercheva-Kyuchukova L, Pylylpenko H et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 2011; 12(13):1204-13.
- Badoux XC, Keating MJ, Wang X et al. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 2011; 118(8):2085-93.
- Parikh SA, Keating MJ, O'Brien S et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 2011; 118(8):2062-8.
- Larson RA, Sievers EL, Stadtmauer EA et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005; 104(7):1442-52.
- Lowenberg B, Beck J, Graux C et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood 2010; 115(13):2586-91.
- Burnett AK, Hills RK, Milligan D et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011; 29(4):369-77.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. v1.2012. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf. Last accessed April, 2012.
|CPT||96409 - 96417||IV chemotherapy administration, code range|
|ICD-9 Diagnosis||200.10–200.18||Lymphosarcoma code range|
|202.00–202.08||Nodular lymphoma code range|
|202.80-202.88||Other lymphomas (including non-Hodgkin lymphoma not otherwise specified), coding range|
|204.10–204.12||Chronic lymphocytic leukemia code range|
|205.00–205.02||Acute myeloid leukemia code range|
|HCPCS||J9010||Alemtuzumab, 10 mg|
|J9310||Rituximab, 100 mg|
|J9300||Gemtuzumab ozogamicin, 5 mg|
|ICD-10-CM (effective 10/1/14)||C82.90 – C82.99||Follicular lymphoma code range|
|C83.50-C83.59||Lymphoblastic (diffuse) lymphoma code range|
|C85.80-C85.89||Non-Hodgkin lymphoma code range|
|C91.10-C91.12||Chronic lymphocytic leukemia code range|
|C92.00-C92.02 C92.40-C92.42 C92.50-C92.52 C96.60-C92.62 C92.a0-C92.a2||Acute myeloid leukemia code range|
|ICD-10-PCS (effective 10/1/14)||ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy.|
|3E0330M, 3E0430M, 3E0530M, 3E0630M||Administration, physiological systems and anatomical regions, introduction, percutaneous, antineoplastic, monoclonal antibody, code by body part (peripheral vein, central vein, peripheral artery, central artery)|
|Type of Service||Oncology|
|Place of Service||Outpatient|
Monoclonal Antibodies, B-Cell Malignancies
|08/15/01||Add to Medicine section||New policy|
|05/15/02||Replace policy||Policy revised; policy statement changed regarding rituximab for intermediate or aggressive NHL|
|04/16/04||Replace policy||Literature review update; added the 2004 US Pharmacopeia and the American Hospital Formulary Service off-label indications to the Benefit Application section; clarification made: mantle cell was removed from investigational status; otherwise, policy statement unchanged|
|7/15/04||Replace policy||2nd sentence in Policy Guidelines section revised to clarify meaning|
|06/27/05||Replace policy||Literature review update for the period of 2004 through May 2005; reference numbers 9-14 added. Policy statement changed to indicate rituximab may be considered medically necessary as first-line therapy for mantle cell, low-grade or follicular non-Hodgkin’s lymphomas|
|10/10/06||Replace policy||Policy updated with literature review though August 2006. Policy statement changed to indicate that rituximab is medically necessary for patients with CD-20 positive CLL. Reference numbers 15-19 added|
|05/14/09||Replace policy||Policy updated with literature review through April 2009; clinical input reviewed. Entire policy extensively revised; policy statements now include FDA-approved indications as well as off-label uses included in national drug compendia. Title changed, “off-label” and “B-Cell Lymphoid Malignancies” taken out; reference list completely revised.|
|05/13/10||Replace policy||Policy updated with literature review; references 24 and 33 updated, references 12, 32 and 34 added. No change to policy statements|
|5/12/11||Replace policy||Policy updated with literature review; references 37 and 52 updated, references 1, 16, 17, 19-22, 32, 35, 36, 38, 39, 42, 43, 51 added. Change to policy statements; addition of a medically necessary policy statement on the use of rituximab as maintenance therapy; addition of ofatumumab to the policy with medically necessary and investigational indications. The term “including Chronic Lymphocytic Leukemia” was added to the title. The medically necessary policy statements for first-line use in follicular lymphoma were modified to indicate “chemotherapy” rather than specific regimens|
|5/10/12||Replace policy||Policy updated with literature review; references 49-51 added.|
|7/11/13||Replace policy||Policy updated with literature review through June, 2013; references 32 and 42 added. Policy statement added that ofatumumab is considered investigational for the treatment of malignancies other than B-cell CLL.|