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ASH Clinical News 101

You Make the Call

Each month in “ You Make the Call ,” we ’ ll pick a challenging clinical question submitted through ASH ’ s Consult a Colleague program and post the expert ’ s response , but we also want to know what you would do . Send in your responses to next month ’ s clinical dilemma and see how your answer matches up to the experts ’ in the next print issue .

This month , Jonathan E . Kolitz , MD , discusses treating a patient with acute lymphocytic leukemia who is of advanced age .

Clinical Dilemma :

An otherwise fit 92-year-old who presented with pancytopenia was diagnosed with Philadelphia chromosome negative ( Ph- ) B-cell acute lymphocytic leukemia ( B-ALL ). I am worried about using anthracycline-based chemotherapy because of his age . I am considering vincristine plus prednisone ( low-intensity therapy ). Would you consider alternative therapies ( e . g ., inotuzumab ozogamicin or blinatumomab ) in the upfront setting ?

Expert Opinion

Jonathan E . Kolitz , MD Professor of Medicine , Zucker School of Medicine at Hofstra / Northwell Hempstead , New York Associate Chief , Hematologic Oncology , Monter Cancer Center Lake Success , NY

Managing an advanced age patient with ALL is challenging . consolidation therapy , maintenance therapy using POMP Less than 10 percent of patients with ALL over age 60 are ( 6-mercaptopurine , vincristine , methotrexate , prednisone ) long survivors . There may be no long survivors among should be given for up to two years , as tolerated . patients older than 80 to 90 years . Older patients with If the ALL blast population expresses CD20 , rituximab ALL are more likely to have comorbidities and adverse could be given during induction and post-remission cytogenetic findings . The Ph chromosome is present in therapy . Its use with standard chemotherapy has been more than 40 percent of older patients with ALL , and its shown to improve event-free survival in CD20 + ALL presence provides a treatment option centered on tyrosine ( GRAALL-2005 study and others ). kinase inhibitor therapy , which may lead to meaningful The use of the bispecific T-cell engager antibody blinatumomab or the immunotoxin inotuzumab in Options for this 92-year-old man with Ph- B-ALL are this setting is appealing ; however , these agents are limited to careful use of active agents compatible with his unavailable to previously untreated patients outside of physiologic state . Weekly vincristine for four weeks along clinical trials . Blinatumomab can have serious toxicities with seven days of prednisone or dexamethasone could associated with cytokine release syndrome , including form the basis of an induction regimen . His age does not neurotoxicity and death . Treatment while in remission absolutely prevent use of an anthracycline if his cardiac may reduce that risk . Inotuzumab can cause sinusoidal function is normal . One may choose to give daunorubicin in the range of 30 mg / m 2 on days one to three of the limiting the ability to use this agent in older patients .

obstructive syndrome , a complication related to age ,

induction followed by pegfilgrastim or daily filgrastim Clinical trials studying the use of these agents with starting on day four until count recovery . I would give chemotherapy and even the sequential use of these prophylactic antibiotic therapy with a quinolone when agents without chemotherapy are in progress or being the absolute neutrophil count is under 500 /µ L . Asparaginase should be avoided because of the risk of severe management of older patients with untreated ALL .

developed . The findings could favorably affect future hepatotoxicity .

If remission is achieved , recurrence is likely to be rapid without further therapy . Several cycles of consolidation therapy are given in younger patients , using regimens like those described in CALGB 8811 , BFM , or MRC UKAL- LXII / ECOG E2993 . Given as prescribed , such therapies I have a patient at 37 weeks of her fourth pregnancy . would most likely lead to prohibitive toxicities even in She has a history of type 2A von Willebrand disease , a fit 92-year-old . Consequently , these regimens can be requiring Humate-P replacement in the prior two adapted using significant reductions in dose or abbreviated schedules . Myeloid growth factors and prophylactic hematuria , and heavy menses prior to last pregnancy ,

deliveries and other bleeding occasions ( epistaxis ,

antibiotics should be used liberally . The MOAD regimen , which required monthly doses of Humate-P 1,450 units ). originally published in 1982 – which uses escalating doses She will undergo vaginal induction delivery in two of methotrexate (“ Capizzi methotrexate ”) with asparaginase rescue , along with vincristine and dexamethasone are as follows : PT , PTT , and fibrinogen are normal ;

weeks . She weighs 161 pounds . Her current values

– can be adapted for purposes of post-remission therapy , factor VIII is 96 percent ; von Willebrand factor substituting leucovorin rescue for asparaginase as the ( vWF ) antigen is 113 percent ; and vWF activity is methotrexate dose is escalated and reducing by at least 34 percent . My recommendations include keeping 50 percent the exposure to dexamethasone . Intrathecal activity level at 100 percent prior to delivery and three methotrexate and / or cytarabine should be given multiple days postpartum , Humate-P 2,400 units 30 minutes times throughout post-remission therapy , as outlined in prior to epidural , then the same dose every 12 hours published trials . The value of prophylactic cranial radiation in this setting is unclear . If the patient is disease-free daily until hemostasis is achieved . Are my dosing

for three days followed by Humate-P 1,450 units toward the end of consolidation therapy , it could be considered . Possible effects on cognition need to be assessed . How would you respond ? Email us at

recommendations correct ?

Finally , if remission is sustained after a few rounds of ashclinicalnews @ hematology . org . ●

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Next Month ’ s Clinical Dilemma :

TRAINING and EDUCATION

Consult a Colleague Through ASH

Consult a Colleague is a service for ASH members that helps facilitate the exchange of information between hematologists and their peers . ASH members can seek consultation on clinical cases from qualified experts in 11 categories :

• Hematopoietic cell transplantation

• Hemoglobinopathies

• Hemostasis / thrombosis

• Lymphomas

• Lymphoproliferative disorders

• Leukemias

• Multiple myeloma & Waldenström macroglobulinemia

• Myeloproliferative disorders

• Myelodysplastic syndromes

• Thrombocytopenias

Assigned volunteers (“ colleagues ”) will respond to inquiries within two business days ( either by email or phone ).

Have a puzzling clinical dilemma ? Submit a question , and read more about Consult a Colleague volunteers at hematology . org / Clinicians / Consult . aspx or scan the QR code .

* If you have a request related to a hematologic disorder not listed here , please email your recommendation to ashconsult @ hematology . org so it can be considered for addition in the future .

DISCLAIMER : ASH does not recommend or endorse any specific tests , physicians , products , procedures , or opinions , and disclaims any representation , warranty , or guaranty as to the same . Reliance on any information provided in this article is solely at your own risk .

We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”

To see how the expert responded , turn to page 101 .

Clinical Dilemma :

An otherwise fit 92-year-old who presented with pancytopenia was diagnosed with Philadelphia chromosome-negative ( Ph- ) B-cell acute lymphocytic leukemia ( B-ALL ). I am worried about using anthracyclinebased chemotherapy because of his age . I am considering vincristine plus prednisone ( low-intensity therapy ). Would you consider alternative therapies ( e . g ., inotuzumab ozogamicin or blinatumomab ) in the upfront setting ?

Because of lack of equipment and medicines , we treat high-risk patients with vincristine and prednisone .

Ahmad Walid Yousufzai , MD Jamhuriat Hospital Kabul , Afghanistan

Summary of Clinical Trial Experience in Diffuse Large B-Cell Lymphoma ( DLBCL )

The data in Table 2 were obtained in the MabEASE study , a comparative , randomized , parallel-group , multicenter study to investigate the efficacy of RITUXAN HYCELA ( 1,400 mg rituximab and 23,400 Units hyaluronidase human ; n = 369 ) versus 375 mg / m 2 a rituximab product by intravenous infusion ( n = 203 ) both in combination with CHOP ( R-CHOP ) in previously untreated patients with CD20-positive DLBCL .

Eighty two percent of patients receiving RITUXAN HYCELA or rituximab completed all 8 cycles of study treatment . In both RITUXAN HYCELA and rituximab treatment groups , patients experienced 4.9 months median duration of rituximab exposure in each arm .

The demographic characteristics were balanced between the two treatment groups . Most patients were Caucasian ( 79 %) and more than half ( 54 %) were male . The study population had a median age of 64 years ( 61 % of patients aged ≥ 60 years ) with median BSA of 1.83 m 2 ( 1.83 and 1.84 m 2 for RITUXAN HYCELA and rituximab groups , respectively ).

The incidences of adverse reactions of any grade ( RITUXAN HYCELA [ 94 %] vs . rituximab [ 92 %]) ( Table 2 ), Grade 3 – 4 adverse reactions ( RITUXAN HYCELA [ 63 %] vs . rituximab [ 57 %]), and serious adverse reactions ( RITUXAN HYCELA [ 42 %] vs . rituximab [ 37 %]) were generally comparable between the two treatment groups . The common adverse reactions ( occurring in ≥ 20 % of patients in any treatment group ) were neutropenia , alopecia , nausea , and anemia .

A total of 91 patients ( 16 %) died , including 58 / 369 patients ( 16 %) in RITUXAN HYCELA and 33 / 203 patients ( 16 %) in rituximab . Of these patients , 44 patients ( 29 patients RITUXAN HYCELA [ 8 %] vs . 15 patients rituximab [ 7 %]) died due to adverse reactions and 35 patients ( 22 patients RITUXAN HYCELA [ 6 %] vs . 13 patients rituximab [ 6 %]) died due to disease progression . Pneumonia ( 4 patients RITUXAN HYCELA vs . 1 patient rituximab ), septic shock ( 2 patients RITUXAN HYCELA vs . 3 patients rituximab ), and cardiac arrest ( 1 patient RITUXAN HYCELA vs . 3 patients rituximab ) were the most common adverse reactions leading to death .

The incidence of administration-related reactions was balanced between the RITUXAN HYCELA and rituximab groups ( 28 % vs . 29 %). Grade 1 – 2 ARRs constituted 97 % of the overall ARRs for the RITUXAN HYCELA arm and 80 % for the rituximab arm . Of the reported ARRs , local cutaneous reactions with RITUXAN HYCELA were reported in 17 patients . These events resolved within a median of 2 days from the onset ( range 1 to 32 days ). Majority of these reactions were Grade 1 and 2 and were observed in 16 patients ( 4 %).

Table 2 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated DLBCL Receiving RITUXAN HYCELA or Rituximab in Combination with CHOP

Body System / Adverse Reactions

RITUXAN HYCELA + CHOP ( n = 369 )

All AEs %

Grade 3 – 4 %

Rituximab + CHOP ( n = 203 )

All AEs %

Grade 3 – 4 %

Table 2 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated DLBCL Receiving RITUXAN HYCELA or Rituximab in Combination with CHOP ( cont ’ d )

Body System / Adverse Reactions

RITUXAN HYCELA + CHOP ( n = 369 )

All AEs %

Grade 3 – 4 %

Rituximab + CHOP ( n = 203 )

All AEs %

Grade 3 – 4 %

Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia

The data in Table 3 were obtained in part 2 of the SAWYER study , a two-part , comparative , randomized , parallel-group , multicenter study of RITUXAN HYCELA versus a rituximab product by intravenous infusion both in combination with fludarabine and cyclophosphamide ( FC ) chemotherapy in patients with previously untreated CLL .

The safety analysis population in part 2 of the study included 85 patients receiving RITUXAN HYCELA ( 1,600 mg rituximab / 26,800 Units hyaluronidase human ) and 89 patients receiving 500 mg / m 2 rituximab . In both RITUXAN HYCELA and rituximab groups , patients had similar median duration of rituximab exposure ( 4.9 vs . 4.7 months ). The majority of patients received all 6 cycles of study treatment ( 86 % RITUXAN HYCELA vs . 81 % rituximab ).

The patient population was predominantly Caucasian ( 96 %), male ( 65 %), with a median age of 60 years and median BSA of 1.9 m 2 ( 1.97 and 1.86 m 2 for the RITUXAN HYCELA and intravenous rituximab groups , respectively ). Overall , the treatment groups were balanced with respect to demographic characteristics , with the exception of more males in the RITUXAN HYCELA arm ( 71 % RITUXAN HYCELA vs . 60 % rituximab ). Baseline disease characteristics were similar between the two groups . Over half of the patients ( 62 %) had Binet Stage B disease and the majority had typical CLL characterizations ( 93 %), with median time from first CLL diagnosis to randomization being 18.5 months .

The incidences of adverse reactions were balanced between the two treatment groups ( 96 % RITUXAN HYCELA vs . 91 % rituximab ), and the common adverse reactions ( occurring in ≥ 20 % of patients in any arm ) were infections , neutropenia , nausea , thrombocytopenia , pyrexia , anemia , vomiting , and injection site erythema . The incidences of Grade 3 – 4 adverse reactions were also balanced between the two treatment groups ( 69 % RITUXAN HYCELA vs . 71 % rituximab ). The incidence of serious adverse reactions was 29 % for RITUXAN HYCELA and 33 % for rituximab . The incidence of administrationrelated reactions was 44 % for RITUXAN HYCELA and 45 % for rituximab ). Of the reported ARRs , local cutaneous reactions with RITUXAN HYCELA were reported in 15 patients . These events resolved within a median of 6 days from the onset ( range 3 to 29 days ). Majority of these reactions were Grade 1 and 2 and were observed in 14 patients ( 16 %).

A total of 9 patients ( 5 %) died , including 5 patients in the RITUXAN HYCELA group and 4 patients in the rituximab group . In the RITUXAN HYCELA group , 1 patient died due to herpes zoster infection , 1 patient died as a result of progressive multifocal leukoencephalopathy ( PML ) ( considered by the investigator as related to rituximab ), and 3 patients died due to disease progression . In the rituximab group , 2 patients died due to diarrhea and listeriosis and 2 patients died due to disease progression .

Table 3 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated CLL Receiving RITUXAN HYCELA or Rituximab in Combination with FC

Body System / Adverse Reactions

RITUXAN HYCELA + FC ( n = 85 )

All AEs %

Grade 3 – 4 %

All AEs %

Rituximab + FC ( n = 89 )

Grade 3 – 4 %

6.2 Immunogenicity As with all therapeutic proteins , there is potential for immunogenicity . The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading .

In the SABRINA study , where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP , the incidence of treatment-induced / enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group ( 2.0 % RITUXAN HYCELA vs . 1.5 % rituximab ). The incidence of treatment-induced / enhanced anti-recombinant human hyaluronidase antibodies was 13 % in the RITUXAN HYCELA group compared with 8 % in the rituximab group , and the overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies