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You Make the Call

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

This month , Michael Deininger , MD , PhD , discusses treatment for a patient with chronic-phase chronic myeloid leukemia ( CML ) whose BCR / ABL transcript levels are rising .

Clinical Dilemma :

A 55-year-old female patient received a diagnosis of chronic-phase chronic myeloid leukemia in April 2016 . After treatment with dasatinib 100 mg daily , major molecular response was achieved in January 2017 . BCR / ABL1 b2a2 increased to 0.99 percent by June 2017 , and dasatinib was increased to 140 mg daily ( BCR / ABL1 kinase domain mutation was negative ). When BCR / ABL reached 0.27 percent in January 2018 , she was changed to nilotinib 300 mg twice a day . BCR / ABL was 0.24 percent in April 2018 , and 0.77 percent in June 2018 . She is healthy and compliant . What should be done next ?

Expert Opinion

Michael W . Deininger , MD , PhD Professor and Chief of Hematology and Hematologic Malignancies Department of Internal Medicine and the Huntsman Cancer Institute University of Utah

Patients with newly diagnosed chronic phase CML have several tyrosine kinase inhibitor ( TKI ) options , including imatinib or one of the second generation ( 2G ) inhibitors : dasatinib , nilotinib , or bosutinib .

During the initial phase of her TKI therapy , this patient ’ s response was optimal , with MMR documented after nine months . Unusual in this situation , she subsequently lost MMR , although she probably maintained a complete cytogenetic response ( CCyR ), given that her BCR-ABL1 transcript remained < 1 percent .

At this juncture , it is important to establish whether the loss of MMR reflects true acquired resistance , lack of compliance , or a fluctuation in the polymerase chain reaction testing for the BCR-ABL1 transcript . Re-testing after 4 to 6 weeks can address such fluctuations and allows reassessment of the transcript levels – and it never hurts to remind the patient of the virtues of strict adherence to the regimen . Unlike loss of CCyR , loss of MMR alone is not necessarily a reason to switch therapy . In the current case , dasatinib was escalated to 140 mg daily , the maximum dose typically prescribed for accelerated or blast phase . Surprisingly , there was little improvement in the BCR-ABL1 level . In fact , a reduction from 0.99 to 0.27 percent is within the variation of BCR-ABL1 testing in many labs , and the two values are statistically not different . The CML in this patient truly seems to be resistant even to high doses of a 2G TKI .

In some cases , switching to another 2G TKI is beneficial , but these tend to be patients in whom adverse events force the drug ’ s dose to be lowered . In this patient , nilotinib did not improve response , with two values hovering between CCyR and MMR . At this point , switching to yet another 2G TKI will not help . Ponatinib , arguably the most potent of the TKIs , might improve the response , but toxicity concerns could be prohibitive .

Checking whether a T315I mutation has developed could be considered , but the likelihood of a positive result is low , given the stability of BCR-ABL1 . Thus , continued monitoring of residual CML and of cardiovascular nilotinib toxicity would be my preferred strategy . An honest discussion with the patient that treatment-free remission in the future is unlikely would be part of this plan . If , with continued monitoring , her BCR-ABL rose to > 1 percent , one should repeat the diagnostic workup , including cytogenetics and mutation screening to rule out nilotinib-resistant mutants . The next step would be treatment with bosutinib , but I would recommend this only if she had a mutation that is likely to respond to bosutinib . With no mutations or with a T315I mutation , one should consider ponatinib or preferably a clinical trial . An evaluation for allogeneic stem cell transplant is indicated , with the understanding that ponatinib or a clinical study should be attempted first . If there was an inexorable rise of BCR-ABL1 or sign of acceleration , then a transplant should be considered , provided the risk is acceptable .

Next Month ’ s Clinical Dilemma :

I have a 22-year-old Vietnamese female patient who moved to the U . S . at around age 10 . She has no pertinent family history . She presented two years ago to an outside hospital with epistaxis and was found to have a platelet count of zero . She was also noted to have abnormal liver function tests , for which workup , including a liver biopsy , revealed autoimmune hepatitis with grade 4 cirrhosis . She responded to immune thrombocytopenia purpura ( ITP )– directed therapy ( steroids , intravenous immunoglobin [ IVIG ] therapy , and platelet transfusion ) and was discharged . She did not follow up regularly , but had two subsequent bone marrow biopsies , the second of which showed megakaryocyte hyperplasia . More recently , she presented in a similar way to how she did two years ago and was treated the same – steroids , IVIG , and prednisone . She was also given one dose of rituximab . Her platelet count increased to 99 × 10 9 / L , but is dropping to 77 × 10 9 / L . What is the best approach to obtain remission ? Is splenectomy the next step ? She is also being referred for possible liver transplantation , so how does ITP treatment factor into the question of liver transplant ? She has no history of alcohol use .

How would you respond ? Email us at ashclinicalnews @ hematology . org . ●

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 :

• Anemias

• Hematopoietic cell transplantation

• Hemoglobinopathies

• Hemostasis / thrombosis

• Lymphomas

• Lymphoproliferative disorders

• Leukemias

• Multiple myeloma & Waldenström macroglobulinemia

• Myeloproliferative neoplasms

• 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 .

ASH Clinical News

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

Read the description of the clinical dilemma here , and see how the expert responded on page 47 .

Clinical Dilemma :

A 55-year-old female patient received a diagnosis of chronic-phase chronic myeloid leukemia ( CML ) in April 2016 . After treatment with dasatinib 100 mg daily , major molecular response ( MMR ) was achieved in January 2017 . BCR / ABL1 b2a2 increased to 0.99 percent by June 2017 , and dasatinib was increased to 140 mg daily ( BCR / ABL1 kinase domain mutation was negative ). When BCR / ABL reached 0.27 percent in January 2018 , she was changed to nilotinib 300 mg twice a day . BCR / ABL was 0.24 percent in April 2018 , and 0.77 percent in June 2018 . She is healthy and compliant . What should be done next ?

Allogeneic hematopoietic cell transplantation ( alloHCT ).

Richard McGee , MD True North Oncology Consulting

Edmonds , WA

ASHClinicalNews . org

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