Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards

ASCO University
Apr 15, 2015 9:56 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Steven Schichman (Central Arkansas Veterans Healthcare) and Clive Zent (University of Rochester).

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Comments

10321

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 15, 2015 9:59 AM

Patient Case

Medical History:  The patient had an incidental finding of leukocytosis with lymphocytosis prior to elective knee replacement surgery in June of 2011 at the age of 79 years. He is a retired baker and lifetime non-smoker whose medical history is negative for diabetes, hypertension, or cardiovascular disease.
 
Laboratory Studies:  WBC 16.9 x 109/L with an absolute lymphocyte count (ALC) of 11.9 x 109/L. hemoglobin 14.5 g/dL, hematocrit 43%, platelets 210 x 109/L.  Red cell indices were normal. Metabolic panel was normal. Review of the peripheral blood smear showed increased numbers of small, mature lymphocytes with occasional smudged cells. Flow cytometry analysis of the patient’s peripheral blood showed a monoclonal population of B cells that expressed CD45, CD19, CD5, CD20, CD22, CD23, and lambda light chain. Expression of CD20 and lambda light chain was dim.  B cells were negative for expression of CD10, FMC7, or CD38.

Diagnosis:  The patient was diagnosed with chronic lymphocytic leukemia (CLL), Rai stage 0 disease.  The patient was followed up every 6 months by his local oncologist.

Clinical Course: The patient was seen by his local oncologist in February of 2013, approximately 19 months after initial diagnosis.  At that time, his WBC had increased to 73.6 x 109/L with an ALC of 68 x 109/L, hemoglobin 10.9 g/dL, and platelet count of 119 x 109/L.  The patient was asymptomatic (performance status 0) with no palpable lymphadenopathy or hepatosplenomegaly. Treatment for CLL was started with standard fludarabine monotherapy (25 mg/m2/d x 5 days every 28 days) and he received 4 cycles of therapy. Chemotherapy was stopped when the patient developed pneumonia. The patient experienced progressive decline in performance status during and after treatment.  

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 15, 2015 10:01 AM

Discussion Questions

  1. Did this patient meet the standard criteria for initiation of therapy for his CLL?  
  2. What genetic tests were indicated prior to initial treatment of the patient’s CLL?
  3. Do you consider fludarabine monotherapy to be a suitable therapy for this patient in 2015?

10326

Anis Toumeh, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 15, 2015 11:49 AM

1- Assuming the anemia and thrombocytopenia are not autoimmune in etiology, then yes this elderly patient with good performance status does qualify for treatment. Although age should generally determine the goal of treatment in CLL, the patient's functional status rather than chronological age can be more informative. Moreover, findings suggest that survival of CLL patients aged >75 years at diagnosis is no different than survival of age-matched healthy controls provided they are fit for treatment.

2- Although treatment options for elderly patients might not be as rigorous as those for their younger counterparts, prognostic information is very helpful at the time of initial treatment and should mainly rely on the standard FISH panel detecting deletions in the 13q, 11q and 17p locations, as well as trisomy 12.

3- I would not consider single agent fludarabine as an appropriate approach for an elderly fit patient and certainly not for an elderly unfit paitnet either. Studies have consistently shown that unless contraindicated, the addition of Anti-CD20 to chemotherapy results in superior outcomes. For this particuar patient I would consider the following ( in order of perference ):

A- Bendamustine - Rituximab / or Ibrutinib if he turns out to have 17p deletion - I would be hesitant to use FCR given his age and the risk of toxicities ( especially if it turns out that he has isolated 13q deletion )

B- Chlorambucil - Obinotuzumab 

C- Chlorambucil - ofatumumab 

D- Single agent Rituximab or Obinotuzumab 

E- Single agent Bendamustine or Chlorambucil 

 

10336

Nitin Jain, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 15, 2015 3:25 PM

1. I dont think this patient met the criteria for treatment. Yes, his hb and plt are decreasing but are still well preserved. He is aymptomatic. He should have been just observed. 

2. He should get CLL FISH panel testing, mutation status of IGVH, p53 sequencing (if avaialble). This is very important because if del17p, patient should receive ibrutinib (again, if meeting treatment indication)

3. First line of older patients depends on  FISh status. If del(17p) - ibrutinib.

If not del 17p - then chlorambucil + obinutuzumab would be the best option (outside of a clinical trial)

10341

Jeff Porter Sharman, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 16, 2015 9:07 PM

1) Patient likely headed for treatment in next several months.  Not totally wrong to jump into therapy before patient is sick and "in need" of therapy, but that is a judgment call.  Note that his lymphocyte count was up 6x over 19 months indicating a fairly fast doubling time.

2) Sadly, data shows that only about 50% of US CLL patients get FISH testing prior to therapy in both frontline and relapsed settings.  This is probably because physicians have less familiarity with the significance of various test results.  In addition to FISH, novel mutation markers including TP53, SF3B1, NOTCH1, BIRC3 predict relative resistance to chemotherapy.  Those patients lacking all negative markers do remarkably well based upon analysis of the German CLL8 study.  On the other hand, it is clear that having adverse marker or bad FISH means such disease unlikely to achieve durable control.  Such labs now available through multiple vendors including Aegis, CGI, and others.  High risk abnormalities definitely much more frequent in the IgHV unmutated population.  Although ibrutinib has labeled indication only in 17P, would also give such therapy in TP53 mutated at current time, and I expect once frontline indication more broadly available, would consider in setting of other high risk markers.

 

3) Fludarabine monotherapy is wrong in many ways.  Drug is cleared through the kidneys, so must be very attentive to decreases in GFR in elderly, even in setting of "normal metabolic panel."  Creatinine of 1.2 is very different in 24 and 74 year old.  In German CLL10 study of FCR vs BR, the PFS curves didn't really separate in the population above age 65  so favor non-fludarabine based regimen and no reason to omit CD20 therapy.  CLL11 shows clear superiority of obinutuzumab over rituximab (if you work with drug much, you probably recognize they are quite different and it isn't a question of different dose).

 

 

Jeff Sharman

http://cll-nhl.com

10346

Kamran Alimoghaddam, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 17, 2015 12:54 PM

1- although doubling time of lymphocytes are low but it seems that patient could be followed without chemotherapy 2- FISH and other molecular tests are not available in many part of the world and we usually should relay to clinical data for decision making and clinical data such as doubling time, performance status and also response to chemotheray guide us for decision making 3- in developing countries we should cosider cost and cost,benefit ratio for decision making so usually we choose cholorambucil + prednisolon for such case with 79 years old age. For young patients We usually cosider FCR or other Fludarabin base treatments. Value of FISH study for us is when we have to decide about possibilty of HSC transplantation.

10351

Grzegorz S. Nowakowski, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 19, 2015 1:11 PM

1. Treatment might be required in next 12 months, however at the time is not mandatory. Careful observation would be OK. Considering progression so far, not it is unreasonable to consider treatment soon, provided other causes of progressive cytopenias are excluded (autoimmune) after discussion with the patient. . 

2. One would consider testing for 17p/p53 alterations. Purine analogues have limited activity in this setting, however, there is limited evidence if treatment with other agents in upfront setting, including ibrutinib.  If 17p del or tp53 alterations are present, due to less toxicity, ibrutinib may be considered. 

3. I would consider CD20 antibodies in addition to chemotherapy. Dr. Zent may disagree with me here, but I would actually consider BR in this older patient over fludarabine or pentostatin combinations, particularly if 17p/TP53 testing is negative.  

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Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 20, 2015 2:36 PM

Did this patient meet the standard criteria for initiation of therapy for his CLL?

Course Faculty Response

Criteria defining “active CLL” requiring treatment are described in the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) revision of the National Cancer Institute Working Group criteria of 1996 (IWCLL 2008). The criteria for initiation of therapy include cytopenia (hemoglobin <11 g/dL or platelets <100 x 109/L) caused by progressive CLL. This patient had a hemoglobin <11 g/dL but there was no evidence to support a diagnosis of bone marrow failure. In patients with CLL, a non-iatrogenic hemoglobin <11g/dL is caused by CLL associated bone marrow failure in only  ~50% of cases. Diagnosis of bone marrow failure thus requires a bone marrow study. Because no bone marrow study was done in this patient, his anemia cannot be confirmed as an indication for initiation of treatment. The patient did not meet any of the other IWCLL 2008 criteria for initiation of therapy for CLL. Of note, the increase in his ALC is not a basis for initiation of treatment. The IWCLL 2008 retains the lymphocyte doubling time as a criterion for treatment. There is insufficient data to calculate the lymphocyte doubling time in this patient. Based on the available data, it is not possible to determine if the patient met criteria for IWCLL 2008 criteria for treatment.

10366

Steven Schichman
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 20, 2015 2:49 PM

What genetic tests were indicated prior to initial treatment of the patients CLL?

Course Faculty Response

Testing for defects in TP53, the gene coding for the tumor suppressor protein p53, should be considered standard of care for patients prior to initiation of therapy for CLL. Interphase fluorescent in situ hybridization (FISH) testing of CLL cells can detect 17p13 deletion that results in loss of one allele of TP53. This deletion is detected in ~5% of patients requiring initial treatment for CLL and is usually monoallelic. The consequences of loss of one allele of TP53 are determined by the integrity of the remaining allele of TP53. TP53 mutations can be detected in clinical laboratories by conventional Sanger DNA sequencing. This technology can detect mutations that occur at an allele frequency of over 10%. Most laboratories sequence exons 4-9 and will detect about 90% of the multiple annotated mutations that occur in TP53 in CLL cells. In ~80% of patients with 17p13 deletion, the remaining TP53 allele has a mutation predicted to be dysfunctional. These patients have disrupted p53 function and have poor responses to chemoimmunotherapy regimens because DNA damaging agents are ineffective in patients without an intact DNA damage response pathway. In ~5% of patients with progressive CLL, TP53 is disrupted in the absence of 17p13 deletion. This may occur due to biallelic mutation, a single mutation with uniparental disomy, or by generation of a dominant negative mutant.

FISH analysis can detect other prognostic recurrent genetic events in patients with CLL. In addition to 17p13 (TP53) deletion, the routinely used FISH probes for CLL prognosis test for 11q22.3 (ATM locus) deletion, trisomy 12, and 13q14 (MIR15 and MIR16 loci) deletion.  FISH abnormalities in CLL should be interpreted using a hierarchical stratification considering only the lesion with the highest risk implications: 17p13 deletion > 11q22.3 deletion > trisomy 12 > 13q14 deletion. Deletions of 17p13 and 11q22.3 predict a higher risk of disease progression and poorer outcomes following therapy.  Deletion of 13q14 (as the sole FISH abnormality) is associated with a lower risk of disease progression and better responses to therapy. FISH using an IGH break apart probe is very useful for detecting those patients with a leukemic phase of mantle cell lymphoma that may have an immunophenotype overlapping that of CLL. Mantle cell lymphoma is characterized by a reciprocal chromosomal translocation (t(11;14)(q13:q32)) that is detected by the IGH FISH probe.

Genome wide analysis using next generation sequencing (NGS) technology has shown that CLL is usually a low complexity genetic disease. These and other studies have shown that recurrent mutations of ATM, NOTCH1, SF3B1, and BIRC3 occur in CLL with prognostic implications. NOTCH1 and SF3B1 mutation analysis are available in clinical laboratories.  NOTCH1 is a signaling protein that regulates gene expression.  NOTCH1 mutation results in a gain-of-function that is associated with more aggressive disease, poorer treatment responses to chemoimmunotherapy (CIT), and a marked increase (~20x) in the risk of transformation to diffuse large B-cell lymphoma. SF3B1 mutations selectively disrupt spliceosome function and are associated with more aggressive disease and poorer treatment responses to CIT. ATM mutation analysis is currently not readily available in clinical laboratories. The clinical consequences of BIRC3 mutations are currently being studied.

CLL cell survival and proliferation require signaling through the B-cell receptor (BCR). The BCR is composed of the cell’s idiotypic immunoglobulin and two accessory signaling proteins Igα (CD79a) and Igβ. The heavy chain variable region of the immunoglobulin (IGHV) is a major determinant of the immunoglobulin antigen binding stereochemistry. B cells activated by antigen IGHV can undergo physiological somatic hypermutation of IGHV in the germinal center of the lymph node. Somatic hypermutation is a complex process that induces mutation in the IGHV sequence that can alter the immunoglobulin antigen binding affinity. Subsequent physiological selection of the highest affinity mutants increases antibody specificity.

Sequencing of IGHV provides valuable prognostic information for patients with CLL. CLL patients with more than 98% IGHV sequence identity to the germline allele are considered to be negative for somatic hypermutation (“unmutated”). These patients have a shorter time from diagnosis to disease progression requiring treatment and a poorer prognosis. In contrast, patients with evidence of somatic hypermutation of IGHV (≤ 98% sequence identity to the germline allele) are considered to be “mutated” and have a longer time to first treatment and a better prognosis.  It has been observed, however, that CLL patients whose malignant cells utilize the IgVH family VH3-21 allele have a poor prognosis irrespective of the somatic mutation status of the IgVH gene.

 

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Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 20, 2015 2:51 PM

Do you consider fludarabine monotherapy to be a suitable therapy for this patient in 2015? 

Course Faculty Response

Management of previously untreated CLL patients with progressive disease requiring therapy should be based on patient fitness and the results of TP53 testing as detailed above.  This patient would be considered to be fit based on performance status and renal function. A more sophisticated functional test (e.g. CIRS) could be of additional value in determining fitness. Although age alone should not be used to determine fitness, a 79 year-old man could have serious complications from a non-curative highly immunosuppressive and potentially myelotoxic regimen such as standard dose fludarabine, cyclophosphamide and rituximab (FCR).

If the patient did not have any evidence of TP53 disruption, he should have been considered for CIT. Sequential randomized controlled trials have shown that fludarabine and cyclophosphamide (FC) was more efficacious than fludarabine alone and that the additional of rituximab to FC (FCR) increased efficacy and overall survival. Subsequent studies have shown improved efficacy and overall survival for the addition of anti-CD20 monoclonal antibodies to chlorambucil or bendamustine. Recent studies comparing bendamustine and rituximab (BR) to FCR suggest that BR is a safer and equally effective regimen in fit patients over 65 years of age. 

In contrast, if the patient did have evidence of disrupted TP53, he is unlikely to have had any substantial benefit from standard chemotherapy or CIT. The current standard of care in the US would be to treat him with ibrutinib, a small molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is FDA approved for initial therapy of progressive CLL in patients with 17p13 deletion. 

10376

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 20, 2015 2:55 PM

Patient Case Update

Physical examination and imaging:  The patient was evaluated at a referral center in December 2013.  At that time, he was not able to walk and had a performance status of 4.  He reported drenching night sweats, more than 10% weight loss over the past 6 months, anorexia, and profound fatigue.  On physical examination, the patient was a pale, frail and wasted elderly man with extensive palpable lymphadenopathy (maximum 2 x 2 cm in the axilla).  His abdomen was mildly distended by a vague central mass.  There was no palpable enlargement of the liver or spleen.  A CT scan of the chest, abdomen, and pelvis showed extensive lymphadenopathy with the largest nodes in the retroperitoneum measuring a maximum diameter of 12 cm.  The scan showed evidence of resolved left lower lobe pneumonia. 

Laboratory studies:  The WBC was 134 x 109/L with an ALC of 130 x 109/L, absolute neutrophil count 2.7 x 109/L, hemoglobin 8.5 g/dL, MCV 107 fL, and platelet count of 164 x 109/L. Creatinine was 0.87 mg/dL with a calculated GFR of 82 ml/minute.  The total bilirubin was 0.4 mg/dL with LDH 209 IU.  Serum protein electrophoresis showed two small paraproteins of 1.4 and 0.5 g/dL with quantitative immunoglobulins of IgG 3195 mg/dL, IgM 136 mg/dL, and IgA 994 mg/dL. Hepatitis B and C serology was negative.  

A bone marrow aspirate and biopsy were performed.  The bone marrow biopsy was 75% cellular with infiltration of CLL cells in a diffuse pattern with approximately 85% lymphocytes.  Proliferation centers were noted.  The biopsy was negative for evidence of large cell transformation of CLL.  Flow cytometry of the peripheral blood showed an immunophenotype that confirmed the diagnosis of CLL.  CLL cells were positive for expression of ZAP-70 (48%) and negative for expression of CD38 (2%)

FISH of the peripheral blood showed a deletion of chromosome 17p13 in 90% of nuclei and trisomy 12 in 21% of nuclei. No abnormalities were detected with FISH probes for 13q14 and 11q22.3 or the IGH locus at chromosome 14q32.3.

Molecular genetic studies for somatic hypermutation showed that the patient’s CLL cells were unmutated (0%) with usage of the IGHV family VH3-48

Standard Sanger sequencing of TP53 exons 4-9 showed a deleterious point mutation (g.17462C>G p.R175G).  High sensitivity NOTCH1 analysis by PCR amplification followed by standard Sanger sequencing (sensitive down to 0.1% of the cell population) was positive for a low level NOTCH1 indel mutation  (c.7541_7542delCT).  No mutations were detected in SF3B1 by Sanger sequencing.

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 20, 2015 2:56 PM

Discussion Questions

  1. What is the differential diagnosis for this patient’s presentation?
  2. Was the evaluation adequate for planning management?
  3. What would be the optimal therapy for progressive CLL in this patient? 

 

10401

Heather Marie Hylton, PA-C
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 24, 2015 9:30 AM

Thank you for posting this interesting case.  For this patient, who has no comorbidities and relatively preserved organ function but a poor performance status and notable frailty, I'm curious know more about his goals of care at this point. 

Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 25, 2015 11:04 AM

Hi Heather - Appreciate this pertinent question. The goals of care depend on the cause of the patients deterioration and the management options for his specific diagnosis. If the patient has been incapacitated by progressive CLL he could respond well to effective CLL treatment. A good response to therapy could also be expected if he has a treatable infectious complication of his CLL. However, if he has transformation to diffuse large B cell lymphoma he is unlikely to benefit from treatment. Unlike some other malignant diseases, many patients with CLL and a marked decrease in performance status can respond very well and have durable responses to treatment. Decisions about the goals of care would have to be made after a discussion of the findings of the appropriate work up with the patient. 

 

10426

Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 25, 2015 11:07 AM

What is the differential diagnosis for this patient’s presentation?

Course Faculty Response

The patient presents with a marked decline in performance status, constitutional symptoms, and extensive adenopathy with increased lymphocytosis and anemia. The most likely causes of this presentation are: 

1) Progressive CLL - The response to therapy with fludarabine in this patient was not fully documented. However, the available data suggests that he did not respond and this presentation is compatible with purine analogue refractory disease. This finding is supported by the detection of 17p13 deletion and a dysfunctional mutation of TP53 (TP53 disruption).  The lack of pre-treatment data means that we do not know if these genetic abnormalities were present prior to initial treatment. Patients with CLL can acquire new genetic lesions in their CLL cells during the course of their disease (clonal evolution) or treatment can result in the expansion of small resistant subclones in the CLL population (clonal selection). The CT scan of the abdomen is useful in documenting the tumor burden. It also confirms that the abdominal mass on physical examination is comprised of retroperitoneal nodes. The bone marrow findings suggest that the anemia is caused by bone marrow failure secondary to involvement by CLL.

2) Transformed lymphoma - The patient’s presentation and clinical findings are compatible with a new diagnosis of diffuse large B-cell lymphoma (DLBCL). This can be caused by clonal evolution of a CLL cell (~80% of cases) or de-novo development of clonally unrelated DLBCL (~20% of cases). The absence of a large B-cell lymphoma in the bone marrow does not exclude this diagnosis. This patient is at increased risk of development of DLBCL because of both TP53 disruption and NOTCH1 mutation. The patient’s presentation is also compatible with the development of Hodgkin lymphoma, which occurs at increased frequency in patients with CLL. Other second lymphoid malignancies should be considered in the differential diagnosis. Patients with CLL have a significantly increased risk of developing solid tissue malignancies. His presentation could be compatible with metastatic disease but this is less likely.

3) Infection - CLL patients, especially those treated with lymphotoxic therapies such as fludarabine, are immunocompromised and susceptible to opportunistic infections. The patient’s presentation is compatible with infections such as tuberculosis and systemic fungal infections (e.g. histoplasmosis). Bone marrow staining and cultures were negative for these infections. 

10431

Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 25, 2015 11:10 AM

Was the evaluation adequate for planning management?

Course Faculty Response

Confirmation of diagnosis: A FDG PET-CT would have provided important diagnostic information in this patient. CLL cells are usually not hypermetabolic and so a negative study would be useful in excluding DLBCL, Hodgkin disease, many metastatic malignancies and systemic infection. If the PET-CT scan showed areas of high FDG uptake (SUV > 5-10), the patient would need an excision (or large incision) biopsy the nodal tissue with the highest FDG uptake. The most likely finding in this patient would be progressive CLL. Patients with progressive CLL and TP53 disruption often have expanded proliferation centers in their lymph nodes that are associated with increased FDG uptake. The distinction between DLBCL and FDG avid CLL lymph node tissue by needle biopsy is unreliable. 

Clonality testing: If the patient has a histological diagnosis of DLBCL, B-cell VDJ gene rearrangement testing on the involved nodal tissue and circulating CLL cells should be done to determine if the two conditions are clonally related. Clonally related DLBCL has a considerably poorer response to treatment and prognosis. 

Anemia: The patient presents with macrocytic anemia. The differential diagnosis of macrocytic anemia is wide and includes nutritional deficiencies (vitamin B12 and folate), myelodysplastic syndrome, DNA damaging drug effect, hypothyroidism, liver disease, and reticulocytosis because of hemolysis or bleeding. The patient did not have reticulocytosis and direct antiglobulin tests were negative with a normal indirect bilirubin level so hemolysis is not likely. 

Paraproteins: The small paraproteins detected in this patient could have been further characterized by immunofixation electrophoresis. Detection of small paraproteins in patients with CLL is common and usually not clinically important. In this patient, this finding only requires follow up. 

10436

Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 25, 2015 11:22 AM

What would be the optimal therapy for progressive CLL in this patient? 

Course Faculty Response

This patient has CLL classified as very-high risk because of TP53 disruption and purine analogue resistance (primary refractory) with poor performance status. However, his poor performance status is most likely due to his progressive disease and is not a contraindication to treatment. The FDA has approved two novel drugs for therapy of relapsed/refractory CLL that are effective in patients with 17p13 deletion. Ibrutinib is a targeted BTK inhibitor that blocks B-cell receptor signaling and prevents CLL cell proliferation. Idelalisib is a targeted PI3Kδ inhibitor that also inhibits B-cell receptor signaling and is approved in combination with rituximab for the treatment of relapsed/refractory CLL in patients considered unsuitable for CIT. Longer-term studies of therapy with ibrutinib have shown that TP53 disruption increases the risk of disease progression on therapy and that many of these treatment failures were manifest as diffuse large B-cell lymphoma. 

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Jeff Porter Sharman, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 28, 2015 6:50 PM

If indeed this patient has relapsed 17P deleted CLL and has not experienced transformation to diffuse large B-cell lymphoma, tyrosine kinase inhibitor would be the most appropriate.  Patterns of care data suggests that Ibrutinib is the most commonly selected agent in this setting.  There is no question that Ibrutinib is a very remarkable drug however there are several items in this particular case to consider that may lead a practitioner to select Idelalisib in combination with rituximab.

In the pivotal study of Ibrutinib versus ofatumumab the median age of patients enrolled in the study was approximately 65 and the fraction of patients with elevated cumulative illness rating scale was only about 60%.  In contrast the study of Idelalisib in combination with rituximab the median age was closer to 71 with significantly higher medical comorbidities as virtually all patients had a cumulative illness rating scale score greater than 6.  In the analysis by John Byrd published in JAMA oncology, the greatest predictor of drug discontinuation for Ibrutinib was patient age.  For the patient's treated at Ohio state university the median age was also approximately 65 years old with a near doubling of drug discontinuation for every additional decade of life.  They presented that approximately 25% of patients had discontinued therapy by 18 months.  This patient seems fairly acutely ill and may not tolerate arthralgias, atrial fibrillation, or bleeding complications.

Additionally in the single arm phase 2 study that led to original approval of Ibrutinib on an accelerated approval basis, the long-term disease control of patients with significantly adversely affected by the presence of either 17P deletion or 11Q deletion.  In the RESONATE17 study which exclusively looked at patients with relapsed CLL and the 17 P deletion the number of prior therapies with significant as was the presence of complex karyotype.  The higher the number of prior therapies or the presence of multiple chromosome changes led to a less favorable outcome.

In the Gilead 116 study in which patients were randomly allocated to rituximab plus or minus Idelalisib, the presence of 17P had no impact on patient outcome for patients who received Idelalisib.  Furthermore, this regimen was looked at in the patients with greatest medical comorbidity.  The impact of age on patient treatment outcome has not yet been reported.

Ultimately either novel therapy would be a very reasonable selection and these agents have never been compared head-to-head however these are some of the features that may be considered that may otherwise be unfamiliar to a practitioner.

10446

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 29, 2015 9:33 AM

Patient Case Update

Based on the high-risk status of the patient with documented 17p13 deletion and TP53 mutation, treatment with ibrutinib was begun in December 2013 at an oral dose of 480 mg daily. The patient had a progressive clinical response to ibrutinib therapy with improved energy and return to performance status of 0 within 2 months. The patient’s lymphadenopathy and abdominal mass were no longer detectible by clinical examination in approximately 1 month.  The ALC increased to a peak of 156 x 109/L at 2 weeks post treatment and then slowly decreased to 6.6 x 109/L in February of 2015. The patient’s hemoglobin has slowly increased to 12.4 g/dL during that time.  The patient has had no complications of therapy to date.

10451

Steven Schichman
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 29, 2015 9:39 AM

Course Faculty Summary

Thanks to everyone for participating in this discussion. In summary, these are my individual interpretations based off of the available information:

  • Genetic testing should be performed at diagnosis for CLL prognosis and prior to initiation of therapy. 
  • The patient in this case had 17p13 (TP53) deletion by FISH analysis.  Deletion of 17p13 predicts high-risk disease because most CLL patients with 17p13 deletion have a TP53 mutation in the remaining TP53 allele.
  • DNA sequencing for TP53 mutations is especially important prior to beginning CLL therapy because deleterious TP53 mutations predict purine analogue refractory disease.  Mutations in NOTCH1 and SF3B1 predict more aggressive disease and poor treatment response to chemoimmunotherapy. The patient in this case was positive for TP53 mutation and NOTCH1 mutation, findings that conferred very high-risk disease.
  • Genetic analysis of CLL cells should include sequencing of the clonal IGVH gene to detect the presence or absence of somatic hypermutation.  The patient’s CLL cells in this case were unmutated for IGVH, reinforcing the high-risk nature of his disease.
  • Genetic testing identifies CLL patients at high-risk whose disease is likely to progress rapidly and require non-standard treatment.

 

10456

Clive S. Zent, MD
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 29, 2015 9:44 AM

Course Faculty Summary

I would also like to thank everyone for this fantastic discussion. Below are my closing thoughts based off of the available information:

  • The patient described in this presentation was an older man who fits well with the demographics of CLL. 
  • He had a short interval between incidental diagnosis and disease progression. This could have been predicted by appropriate genetic testing at diagnosis. IGHV mutation status does not change during the course of CLL. However, early evaluation could have missed the 17p13 deletion and TP53 and NOTCH1 mutations if they were only present in small subclones below the level of detection by current standard assays. 
  • Detection of TP53 dysfunction genetic testing prior to initiation of initial therapy would have predicted failure of a fludarabine based therapy
  • Very-high risk CLL is present in only about 10% of patients at the time of initial treatment. However, early recognition and risk stratified therapy is important for optimal management and outcome.

10461

ASCO University
Re: Chronic Lymphocytic Leukemia (April 2015): Molecular Oncology Tumor Boards
Apr 29, 2015 9:49 AM

Thank you to Drs. Schichman and Zent leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-May for a new case in this series related to gastrointestinal cancers.  
 


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