Dear Dr Collins - Introduction and Case 1

Welcome to Dear Dr Collins

The aim of this is to share some of the challenging lymphoma cases I get asked to comment on, usually via email. I am very aware of the need for patient confidentiality so although the cases will be based on real ones, details will be changed so that it will not be possible to identify patients from the clinical details listed. All the cases discussed are no longer active (at least in my email in box!), so comments in this blog will not be fed back to the treating clinicians so we can speak freely. However we are all, always learning so of course your comments may inform us as we endeavour to treat our patients better and improve their lymphoma journey experience. 

It would be GREAT if people could comment on the cases whether:

- you are a physician: what treatments would you suggest? What is your evidence base? What is your personal experience?
- you are a nurse of physician associate: what has been your experience caring for these patients? Can you share advice on coping with a certain treatment strategy?
- you are a patients or carer: have you faced similar treatment? How did you find it? Can you share personal anecdotes of how to cope better with it?

CASE 1

Dear Dr Collins

Could I ask your help please. I have a 65 year old man who presented with stage IIIA diffuse large B-cell lymphoma. He presented with a lump in his neck which was growing quickly and he had quite profound fatigue. Performance status was 1. He was also off his food but had only lost 5% of his body weight over the last few months. His LDH was raised (550 IU/ml) and his International Prognostic Index (IPI) was 3 at diagnosis. He had 1 cycle of R-CHOP but then his cytogenetics came back showing a translocation involving c-myc and Bcl-2 i.e. a double hit. We switched him to DA-EPOCH-R and are planning 6 cycles. He's had 2 cycles so far and is tolerating it very well. His symptoms have improved and his lump has shrunk although he's not been scanned during treatment. I would be interested to hear your views as to whether there is a role for stem cell transplantation as a consolidation in first remission. If so, would you use an autologous or allogeneic transplant?

His only past medical history is hypertension well controlled on ramipril.

Please do comment!

Discussing CAR-T therapy in practise

CAR-T cell therapy is a very exciting treatment modality for patients with a number of haematological conditions. It is in its infancy and we're likely to see an explosion of new products coming into trials and then into the clinic. I'm focusing here on relapsed and refractory diffuse large B-cell lymphoma.

What are CAR-T cells?

CAR stands for 'Chimeric Antigen Receptor'. Basically, T-cells are immune system cells which can be taken out of the body in a fairly simple way by a process called apheresis (similar to how we get stem cells from patients). Once collected, they can be sent to specialised laboratories where they can be genetically engineered to produce a receptor on the cell surface (a Chimeric Antigen Receptor) which makes the T-cells recognise lymphoma cells. Currently, the protein they are made to recognise on lymphoma cells is called CD19. This is also found on normal B-cells. The T-cells are then grown in the lab, sent back to the patient and re-infused. Just before this, the patient receives some chemotherapy which enables a 'niche' in which the new T-cells can grow. Once inside, the T-cells can hunt down the lymphoma, attack it and also expand in numbers. This is why they are often called a 'living drug' in that the cells can potentially survive and grow within the patient.

How good are they?

In early trials of patients with difficult diffuse large B-cell lymphoma which has come back several times despite good treatment, about 60-70% of patients had a response i.e. their lymphoma shrank by more than 50% in volume. What's more, around 30-40% had a fairly long lasting complete response i.e. there was no detectable lymphoma on a PET scan. This is a very good response for patients with this sort of difficult disease. However we must remember that patients who are eligible for trials don't necessarily represent all patients. When used in the so-called 'real world', some centres have replicated the trial results, whereas others (notably the early data coming from the UK) have not.

What are the problems with CAR-T cells?

There are several.

1. Relapse. This is the most common problem with CAR-T cells. Although the response rates are higher than with other agents seen in this setting, most patients who receive the cells do not benefit in the medium to long term. It is important this is explained to patients. Some people relapse because the lymphoma cells lose the target for the CAR-T (so called CD19 negative escape) whilst others don't work well because the lymphoma cells produce proteins which are immunosuppressive (such as PD-L1). However there are also unknown mechanisms. Much work is underway to try to circumvent these resistance mechanisms.

2. They can cause side effects which in some cases are serious. In particular, cytokine release syndrome is when the T-cells work almost too well so that as they grow and attack the lymphoma they release chemicals into the blood. This can feel like very bad 'flu and can cause the body's blood pressure to drop. This in turn can threaten vital organs such as the kidneys. Sometimes patients need support in the intensive care unit, and an antidote drug called tocilizumab. The other main side effect is neurotoxicity. For reasons we don't properly understand, the CAR-T cells seem to irritate the brain in some patients causing side effects such as confusion, problems with writing or speaking and even coma and brain swelling (although this is not common). Usually these side effects are reversible but some occasional deaths have been reported.

3. The long term effects are unknown. We haven't been using CAR-T cells for long and there maybe long term unwanted side effects. This is NOT a reason not to use them, but it is a reason for continued data collection on the initial patients given these cells, and underlines the need for an appropriately cautious tone as the therapy is described to patients.

4. In some instances, patients have to travel far from home to get the cells. This is really important as most patients who get the cells will relapse and if this happens life expectancy is often short. It is far from ideal for a patient who maybe in the last few months of their life, to be in a hospital, suffering sometimes severe side effects, far away from home, with few visitors due to travel distances. Unfortunately currently we cannot predict which patients will do well and which will do poorly.

What does this mean in practise

CAR-T cell therapy does represent an important advance and offers probably the best chance of a response and of a durable remission for patients with multiply relapsed high grade lymphoma. It is important that this therapy is discussed with potentially eligible patients. However they must be discussed within the right context and other options outlined in detail. Other options for patients include:

(i) Clinical trials. Although by definition, the outcome of a trial is unknown, these maybe available closer to home and maybe using agents with already proven activity such as bispecific antibodies or an anti-CD47 antibody combination. These agents however are unlicensed.

(ii) Alternative chemotherapy approaches. Although unlikely to produce meaningful benefit, some combination such as bendamustine, rituximab and polatuzumab do appear promising. Whilst not wanting to suggest it's curative, remissions are frequent and fairly durable in some. If reimbursed, treatment would be able to be close to home for most patients.

(iii) Supportive / palliative care. It's really important we discuss this as an option with patients. Several times I have recommended a patient has no further active treatment and I've been surprised by how well they do - living with a very good quality of life, ticking off 'bucket list' items and living for longer than I expected. It enables good quality time with family and the necessary sorting out of affairs. It's important not to suggest this is 'giving up' but simply moving to a different phase of treatment whereby the disease isn't the focus, but the symptoms it produces and impact on quality of life are.

Conclusion

CAR-T cell therapy is here to stay. But it's not right for all patients and a major strand of research should be trying to delineate the patients likely to do well and to do poorly with this approach. For now, let's be appropriately cautious in our conversations with patients considering this therapy - not to take away hope, but to present all the options in a fair and balanced way helping the patient to make the right decision for them.

Front line Hodgkin: taking it to the patient

Hodgkin Lymphoma happily has been on the receiving end of many well conducted, randomised phase III clinical trials. Yet in the rather small world of physicians treating advanced Hodgkin lymphoma there is still heated debate on whether to initiate treatment with the fairly potent and relatively well tolerated regimen ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or whether to initiate therapy with the most effective regime we know of for curing the disease albeit with an increased toxicity profile: escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisolone). Opinions tend to fall along geographical boundaries with escalated BEACOPP favoured by Germany and central Europe and ABVD favoured by most of the rest of the world. Since the ECHELON-1 trial, which showed a modest improvement of AVD+Brentuximab vedotin versus ABVD, some of North America has switched to this regimen although it has had little impact on the rest of the world. 

The purpose of this post is to encourage all those who treat Hodgkin lymphoma to involve the patient in the decision as to whether to use ABVD or escalated BEACOPP (or escalated BEACOPDac where the procarbazine is relapsed with dacarbazine) as initial treatment. As physicians we tend to assume we know what's best for the patient yet with the frontline treatment of Hodgkin lymphoma there are genuine options, and the concerns and priorities of the patient are important in determining which regimen is right for the particular patient in front of you. 

What can we say with confidence to patients with advanced stage Hodgkin about to start treatment with one of these two regimens?

ABVD:

• Consistently in trials, 6 courses is associated with a long term PFS (ie. cure rate) of about 75%. Even in the RATHL study which was a response adapted trial, the 5y PFS for all patients was just below 80% and a significant proportion of patients in that study had stage II disease. So 75% still seems about right. 
• In advanced stage disease, patients will receive 6 courses which delivers 300mg/m2 of doxorubicin and in epidemiological studies, this does increase the risk of heart problems (mainly cardiac failure) by about 4 fold.
• In the RATHL study, for the 85% achieving a PET negative scan after 2 cycles, the bleomycin can be safely omitted and the observed pneumonitis rate in these patients is very low indeed
• There is a very low reported rate of second cancers such as AML or MDS but the risk is not zero (I usually quote 1% or less).
• There seems to be a negligible risk on female fertility, although there is still a possibility that it could bring forward the menopause in some patients.
• 6 courses takes 6 months which is very disruptive for especially young patients who maybe at school, university, starting out on their career or raising a family.
• Importantly, the RATHL study did NOT confirm that intensifying to escalated BEACOPP would overcome the negative prognostic significance of a positive interim PET as the PFS in that group was relatively poor. It maybe that group did better than historical patients, but it's very hard to be certain in the absence of a randomisation for those patients in the trial.

Escalated BEACOPP:

• Consistently in trials (such as HD18 and AHL2011), 6-8 courses of escalated BEACOPP is associated with a long term PFS (and therefore cure rate) of 86-90% which is greater than in any ABVD trial in a similar patient population. 6 courses is as effective and less toxic than 8. 
• 2 response adapted trials have shown that in patients achieving an interim negative PET scan, de-escalation is safe; this can be to either 2 more (rather than 4 more) courses of escalated BEACOPP (HD18) or to 4 courses of ABVD (AHL2011). 
• If an HD18 approach is being followed and the patient achieves a negative interim PET scan, their treatment will take just 3 months in total (although it may take longer to recover from than ABVD). 
• 6 courses of escalated BEACOPP delivers 150 mg/m2 (significantly less than ABVD) meaning that the risk of late cardiac effects is likely to be less.
• However, there is a significantly higher rate of febrile neutropenia, neuropathy and requirement for blood products.
• The impact on fertility is also significant. In a female in her 20s, the risk of reduced fertility is around 20%, rising to over 50% in the over 40s. These figures are for 6-8 cycles of the regimen, the effect is less clear when smaller numbers of courses of used, as they are in many patients now with a response adapted approach. 
• There is also an increased risk of 2nd cancers although this remains a small risk (1-3%).
• It is not recommended to give escalated BEACOPP to any patient over the age of 60 and be cautious in patients over 50 or in those with a poor performance status or significant co-morbidities. 

In many centres that use escalated BEACOPP, they are replacing the procarbazine with dacarbazine. This is based largely on paediatric data that showed that switching COPP (cyclophosphamide, vincristine, procarbazine and prednisolone) to COPDac did not have any impact on survival rates, and significantly improved fertility in surviving patients. Although it might be predicted that the same would happen with changing escalated BEACOPP to escalated BEACOPDac, caution needs to be exercised here as there is no data suggesting equivalent outcomes or improved fertility. As there are still big doses of cyclophosphamide, reduced fertility may still be an issue. 

Discussing with the Patient

In medicine, it is important not to assume we know what the patient needs. The front line treatment of advanced cHL is an excellent example. If we have a 20 year old woman in front of us, we may think that ABVD offers the best balance of efficacy and tolerability (including fertility preservation). However, by recommending ABVD we are suggesting a regimen which is associated with at least an absolute 10% increased risk of relapse according to the trials. In some patients I have spoken with, their absolute priority is to cure the disease and the risk on subsequent fertility, or short term toxicity, is of little importance to them. Although relapsed Hodgkin lymphoma can be cured in a reasonably high number of patients, the fear of relapse for some patients is very real and should not be underestimated. In this case I would suggest that to give ABVD is not in the best interests of that individual patient. In an interesting study by Brocklemann et al,  patients (some before, some during and some after treatment) were asked to rank the importance of factors they deem as important when associated with a particular chemotherapy regimen for Hodgkin lymphoma. Cure rate was, not surprisingly, ranked highest. Other factors are important too and I have also looked after other patients with advanced cHL who have opted for ABVD as an initial approach, in order to maximise time as an out patient and to preserve fertility. This is a reasonable approach in these patients and in my view escalated BEACOPP would not seem the correct initial treatment for these patients. 

Discussion with the patient to this level of detail does take time. And in some cases patients simply want to be told what the doctor feels is in their best interest, and they will then comply. This of course is their right. But especially for young patients, where the choice of chemotherapy regimen impacts on more than simply cure rate, it is our duty to spend the time explaining the options and supporting their decisions. 

Identifying those at highest risk

In order to inform the decision between an ABVD based approach, or an escalated BEACOPP based approach, it would be ideal to accurately be able to estimate what the chance of cure with each approach would be at the time of diagnosis, for the individual patient in front of you. Unfortunately though, all we have available currently is the international prognostic scoring (IPSS) otherwise known as the Hasenclever index. This score integrates a number of clinical and laboratory parameters. However it can be difficult to apply. For example, it is quite common for the albumin of a patient to be 39 g/l one day, and 41 g/l 2 days later (probably due to laboratory variation). In the IPSS, one mark is given for an albumin of < 40 g/l. Would this patient score a mark here or not? Furthermore, the IPSS does not seem to prognosticate amongst advanced cHL patients treated initially with escalated BEACOPP. And although there was a prognostic significance seen statistically in the RATHL study, the differences were not great. We are therefore poor at identifying patients at high risk of treatment failure. The Vancouver group did report on a 23 gene signature which appeared promising in identifying those patients likely to relapse with ABVD based treatments, but this was not validated when tested on other patient series. The assessment of metabolic tumour tumour volume by FDG-PET scanning may help prognosticate, but requires further study. 

Our approach in Oxford

Due to the slightly lower overall survival for patients with IPPS 3+ treated on the RATHL study, and the absence of an impact of IPSS seen in escalated BEACOPP treated patients, we tend to recommend an ABVD (RATHL) approach for those with IPSS 0-2 and an escalated BEACOPP approach (HD18) for those with IPSS 3+. However as stated above, this is always in discussion with the patient and we have certainly had patients with a rather borderline IPSS of 3 opt for both escalated BEACOPP and ABVD. The escalated BEACOPP patient wanted treatment finished as quickly as possible so he could return to his studies whereas the ABVD patient placed a high value on preservation of her fertility. We have developed some patient-friendly material to use in clinics to help illustrate some of the points here. Clinical nurse specialists play a vital role in helping patients understand the material, to consolidate their understanding and to apply it to the patient's life circumstances. 

To conclude, randomised trials have provided very useful data for treating patients with advanced Hodgkin lymphoma. However, one size definitely does not fit all and it is important that our practises have the flexibility to offer ABVD or escalated BEACOPP based regimens, that we take time in our consultations to discuss these approaches in ways the patient understands and to not assume we as physicians know what is best.  

Why More is not always Better

The frontline treatment of Diffuse Large B-cell Lymphoma (DLBCL) is becoming somewhat of a graveyard for randomised phase III clinical trials. The last major breakthrough came when rituximab was added to CHOP chemotherapy (see previous post). Since then, a number of approaches have been taken to try to improve outcomes, but they have by and large failed. 3 broad approaches have been pursued, with some overlap:

1. Intensify treatment (especially for patients with high risk disease)
2. Add something to the R-CHOP backbone
3. Use biological stratification to target a new agent or approach to those likely to respond

1. Intensify treatment

This first approach hasn't yet yielded much meaningful fruit. It's easy to comment in retrospect but perhaps this isn't too surprising. My favourite clinical trial of all time was published by Richard Fisher and colleagues in 1993. This study was performed to evaluate claims from phase II studies that their new intensive regimen appeared better that CHOP. We hear similar claims today of course. The study compared 8 courses of standard CHOP chemotherapy with 3 intensive regimens: ProMACE-CytaBOM, MACOP-B and m-BACOD. The result was that all were equally effective whilst CHOP had fewer side effects, was cheaper and safer. In subsequent letters it was noted that the results for ProMACE-CytaBOM and MACOP-B were about 30% lower that in the previously reported phase II studies, providing ample reason for insisting on randomised phase III data before a more intensive and toxic regimen is introduced as standard of care. 

More recently, Dose Adjusted (DA) EPOCH-R (etoposide, prednisolone, cyclophosphamide, doxorubicin and rituximab) was developed by the National Cancer Institute in the US for the treatment of aggressive non-Hodgkin lymphoma. The regimen is a model of scientific logic. Lymphoma cell lines are killed more effectively when longer drug exposure occurs, rather than short boluses hence a key part of this regimen is a 4 days continuous infusion. The addition of etoposide also increased cell kill in vitro. Perhaps the most important aspect though is that it takes seriously the observation that different patients handle drugs differently and that patients who excrete chemotherapy drugs rapidly may not have enough exposure to the components of a bolus regimen. The doses of subsequent cycles are therefore titrated according to the nadir neutrophil count of the prior cycle, providing a biomarker for drug exposure. Sufficient myelosuppression indicates that sufficient chemotherapy drug levels have been achieved leading to biological activity within the individual at a given dose of cycle. Phase II studies appeared promising. However, Bartlett and colleagues have recently published the Alliance/CALGB 50303 study which was a well performed study compared R-CHOP with DA-EPOCH-R in the front line treatment of DLBCL. There was no difference in the primary endpoint of progression free survival (PFS) and the toxicity of DA-EPOCH-R was clearly greater than for R-CHOP. This underscores the point that any new regimen must be tested in this way and I congratulate the US groups for doing just this. The point has been made that a clinically meaningful benefit maybe seen in high risk patients. This is true, but for a regimen which is more toxic and less convenient for patients and physicians, this needs to demonstrated in a comparative trial powered to answer the question. 

2. Add something to the R-CHOP backbone.

A number of studies have looked at, and are looking at R-CHOP+X. One of the recent, large studies reporting on this approach was the Phoenix trial which randomised non-GCB cases (defined by immunohistochemistry which isn't ideal as only gene expression profiling can really define cell of origin) to receive either 6-8 courses of  R-CHOP or 6-8 courses of R-CHOP+ibrutinib (a BTK inhibitor). No difference was seen in the primary endpoint. On further evaluation of prior defined subgroups, younger patients did seem to benefit whereas older patients seemed to suffer from more side effects of the combination leading to a reduced dose intensity of immunochemotherapy and increased relapse rate. However as the trial was not powered to look at this group alone, the combination will not receive a license. The REMODL-B trial from the UK assessed the addition of bortezomib to R-CHOP in cycles 2-6 in a randomised phase III and again no benefit was found.

On-going trials include the ROBUST study, a randomised phase III trial of R-CHOP versus R-CHOP plus lenalidomide in gene expression profile-defined ABC subtype of DLBCL. The trial was based on the observation of phase II studies which seemed to show that R-CHOP+lenalidomide overcame the worse outcomes seen in the ABC subtype when treated with R-CHOP. Results are awaited. The POLARIX study is also an ongoing randomised phase III trial but this time comparing R-CHOP with R-CHOP + polatuzumab vedotin, the antibody-drug conjugate targeting CD79b. There is much hope that this trial may lead to a positive result, in view of a randomised trial of bendamustine rituximab (BR) vs BR + polatuzumab in relapsed / refractory DLBCL showing a PFS and OS survival advantage. However we need to wait until these trials are recruited and published with appropriate follow up. Watch this space!

3. Use biological stratification to target a new agent or approach to those more likely to respond

The Phoenix trial attempted this by only randomising those with non-GCB subtype by immunohistochemistry. One flaw with this approach is that it's far from proven that ibrutinib is significantly more effective in this subtype. A small trial in relapsed / refractory disease did show an enrichment for responses in non-GCB subtype, but this is a long way off showing that the combination of R-CHOP + ibrutinib is only going to work in the non-GCB subtype in the upfront setting. The UK REMODL-B trial in my view performed a better study. Although they predicted that bortezomib would work better in the ABC subtype, all patients were randomised and interim analyses were performed during the trial to see in the randomisation into the GCB subtype could be stopped. This did not happen and indeed on subgroup analysis the only real signal of possible improved outcome with the combination was in those patients with a so-called 'molecular high grade subtype' which is largely found in GCB cell of origin patients. There is a lot of belief surrounding the power of biomarkers but they need to properly tested to determine their true potential for directing therapy.

Another approach is to identify those patients not responding well to R-CHOP and to switch to an alternative strategy. The PETAL study identified such high risk patients with an interim PET scan after 2 cycles of R-CHOP. For those with a positive PET scan, patients were randomised to continue with R-CHOP or switch to a Burkitt-lymphoma type of intensive regimen. No benefit was found with the more intensive treatment but more toxicity was certainly evident.

To conclude, R-CHOP gives very good results for many patients with DLBCL. However those who do not respond well have biologically difficult disease and it's proven difficult to improve outcomes despite numerous attempts. This does not mean we should give up trying. Not at all - randomised phase III trials of promising agents are necessary to make progress. But let's demand these trials to be performed before recommending changes in the standard of care, especially when the new therapy is more toxic than the old. Let's learn from Fisher et al, NEJM 1993.

CHOP: the King of Chemotherapy

The commonest chemotherapy regimen in lymphoma medicine by far is CHOP. This is an odd acronym and takes some explanation. The drugs included are Cyclophosphamide, Doxorubicin (this is the red drug and is otherwise called Hydroxydaunorubicin, hence the 'H'), Vincristine (which comes from the Madagascan Periwinkle hence the vinca plant symbol for Lymphoma Action - otherwise known as Oncovin, giving the 'O') and Prednisolone. 

CHOP exemplifies the principles behind combination chemotherapy. Imagine the days before combination chemotherapy, sitting down in a bar with some colleagues trying to work out which drugs to put together. The following principles are helpful to guide the final result:

- each individual drug should be active in the disease of interest

- the mechanism of action (and therefore of resistance) of each agent should be distinct

- each agent should work at a different part of the cell cycle

- each agent should have distinct (and preferably non-overlapping) dose limiting toxicities enabling the delivery of each drug at near maximal dose

- the pharmacokinetics should not interfere too much with each other

The table below demonstrates how CHOP (combined with rituximab) exemplifies this approach. Under toxicity, 'Myelo' means myelosuppression i.e. low bloods counts (neutropenia etc) and DLT stands for dose-limiting toxicity. You'll note that some of the drugs are cell cycle non-specific which means they act on cancer cells irrespective of whether they are actively cycling or not. Since in any given cancer, usually a minority of cells are actively cycling (high grade lymphoma often being an exception to this rule), including a cycle non-specific drug in a regimen is highly desirable. 

Drug	Action	Cell cycle	Toxicity
Rituximab	Anti-CD20 mAb	Cycle non-specific	No DLT
Cyclophosphamide	Alkylating agent	Cycle non-specific	Myelo (also bladder)
Doxorubicin	Intercalates DNA	S-phase	Myelo (also heart)
Vincristine	Anti-metabolite	M-phase	Neuropathy
Prednisolone	glucocorticoid	G1 phase	Metabolic / neurol

CHOP was initially used for high grade non-Hodgkin Lymphomas. This was in the era before pathologists had immunohistochemistry, so physicians were blind to whether they were treating B-cell or T-cell NHL. With the advent of immunostaining, and then with therapeutic monoclonal antibodies, rituximab was added to the CHOP regimen in high grade B-cell lymphoma (initially diffuse large B-cell lymphoma, the commonest subtype). Results were dramatic with a notable prolongation not just in remission lengths, but also in overall survival. This was first demonstrated by Coiffier et al (who sadly recently passed away) in patients aged 60-80. 

Prof B Coiffer

He performed a randomised study comparing 8 cycles of CHOP with 8 cycles of R-CHOP. Long term follow up of this study is shown graphically below and is taken from Coiffier et al (2010) Blood. The 10 year overall survival rose from 27% to 43% - a massive 16% absolute increase. Since then, adding rituximab to this regimen has cured 1000s of people of their diffuse large B-cell lymphoma. 

Overall survival with 10 years of follow up

CHOP and R-CHOP also have what physicians often describe as an acceptable safety profile. Of course it is really up to the patient to say whether the side effects are 'acceptable' or not. But generally what is meant by this is that it is delivered as an out patient, it is safely given to patients even as they get older (certainly up to 80 years of age) and patients mostly report that the side effects improve with time after finishing. Common side effects include:

- Infusional reactions due to the rituximab (this is quite common but usually only happens with the first dose; subsequent doses are often much less affected.

- Fatigue: a common complaint, often under-estimated by doctors and for which we can do very little. Sometimes this can also be prolonged, interfering with recovery after chemotherapy.

- Hair loss: due largely to the doxorubicin, this is pretty much invariable although it does grow back afterwards (and is frequently different from before - sometimes curly and sometimes even a different colour!)

- Neuropathy: due to the vincristine. Symptoms are usually mild with numbness and tingling in the finger and toes. If it gets worse (starting to interfere with function) then the dose should be reduced. Usually it does recover although not always completely and it can take up to 2 years to get the most recovery. Beware giving vincristine to someone with foot drop as this could be an indication of an underlying hereditary neuropathy which maybe dramatically unmasked when this drug is administered!

- Heart damage: due to the doxorubicin. This is less common but is probably underestimated. 6 courses gives a cumulative dose of doxorubicin of 300mg/m2 which probably increases the risk of heart failure over the years by several fold. 

- Infection risk: the 2nd of the 3 weeks in a cycle is usually characterised by neutropenia. Neutropenic fever (which is medical emergency) happens in about 15-20% of patients on R-CHOP and usually necessitates hospital admission. This frequency can be reduced by the use of G-CSF injections and prophylactic antibiotics.

- Nausea: thankfully we have excellent anti-sickness drugs now so debilitating nausea is uncommon.

- Taste change: this is common although the mechanism isn't clear. Patients often describe a metallic taste and they can go off foods which they previously enjoyed such as curry or coffee. It usually does reverse at the end of treatment but it can take some time.

- Mood changes and raised blood sugars due to the prednisolone. It is important to tell diabetics to monitor their blood sugars more closely and they may need to alter their anti-diabetic medication when on R-CHOP. 

There are numerous other side effects reported, but these are the main ones and the ones I discuss with patients. I also explain that there is a small risk of dying on chemotherapy, but R-CHOP is generally considered a safe chemotherapy and the risk is 1% or less for most people. Certain groups do have a higher risk though, such as the elderly, and those who have had a previous organ transplant. The cause of death is often infection and it's often when people haven't told us they are unwell with a fever, so contacting the medical team for advice quickly is important when on chemotherapy. 

R-CHOP is generally given once every 3 weeks. Before the introduction of rituximab, the German High Grade Lymphoma study group found that administering CHOP every 14 days was a little more effective. In oder to deliver this schedule, they had to routinely give all patients GCSF injections and also additional preventative antibiotics (against an infection called PCP). Once rituximab was introduced it was controversial whether there was any benefit with the 14 day administration. This issue was largely settled by a UK study comparing R-CHOP given every 21 days with every 14 days. The study was led by Professor Cunningham of the Royal Marsden in London and showed equivalent outcomes. This is illustrated by the graph below taken from Cunningham et al (2013) Lancet. 

R-CHOP-21 therefore has remained standard of care. Many attempts to better R-CHOP have been made and have largely failed - but I will blog about that in a subsequent post. 

For now, R-CHOP in my view is the King of Chemo, exemplifying the principles of combination chemotherapy, resulting in excellent outcomes for the majority of patients with high grade B-cell non-Hodgkin lymphomas and all with side effects which, although sometimes severe, are generally tolerable. Of course R-CHOP isn't right for everybody but it remains the gold standard regimen world wide for most with the commonest forms of lymphoma.  As I say to my trainees - if someone asks you how to treat someone with lymphoma, you'll not usually be too far wrong saying R-CHOP-21. 

Where Chemo Comes from

Chemotherapy gets a bad press. It undoubtedly has sometimes severe side effects yet it has saved 100s of thousands of lives from premature cancer deaths. The history of chemotherapy is very interesting. What I'm going to present here is a commonly told tale and I think mostly true, but I really can't vouch for all the historical details.

World War I was full of horrors, perhaps none more horrific than the use of chemical weapons. When World War II broke out, the allies were fearful of its renewed use so they stockpiled a store of mustard gas to use as retaliation. The SS John Harvey had a secret store of mustard gas and was stationed in Bari harbour, Italy when it was subject to an air-raid. Many hundreds of people died due to exposure of released mustard gas. Post-mortem examination of the bodies showed profound lymphoid and myeloid hypoplasia leading physicians to hypothesise it may have therapeutic use in cancer. Two pharmacologists, Goodman and Gilman (picture below), modified the chemical structure of mustard gas to make the more stable nitrogen mustard. Trials on humans with lymphoid malignancies (yes - lymphoma blazed the trial!) showed it could induce temporary responses.

So proof of principle was demonstrated. Shortly afterwards, the pathologist Sydney Farber (of Dana-Farber fame - picture below) reasoned that as the bone marrow in folic acid deficient patients had similarities to the bone marrow of children with acute leukaemia, treating leukaemia with folic acid may have therapeutic benefit. Sadly he was wrong and in fact the exact opposite was observed! Thankfully though Farber had also heard of the recent development of folate antagonists and correctly reasoned that if folic acid made things worse, anti-folates might make things better. Initially aminopterin was used but later methotrexate. Impressive responses were seen in children with ALL and later on in other cancers such as choriocarcinoma.

In a different medical field, experience in infectious diseases suggested that cures for TB could be achieved using combinations of antibiotics to avoid resistance. So it was reasoned that combinations of chemotherapy may achieve similar effects with cancer. Combination chemotherapy was born. Some of the first combination chemotherapy regimens shown to cure cancer, were developed in the lymphomas such as MOPP (in Hodgkin Lymphoma) and later CHOP (in high grade non-Hodgkin lymphoma).

So in a very real sense we have chemical weapons to thank for the development of chemotherapy - a wonderful unintended consequence of a tremendous evil.

Lymphoma - an introduction

This is my first post as a blogger!

Why a lymphoma blog? Lymphoma is a disease which in my view is endlessly fascinating. Some people don't like to use the term 'fascinating' when it comes to a disease as clearly for those affected, it is a source of worry, stress and illness. I don't want to minimise this at all. However, if you are affected by a disease then it is much better to have a specialist who is interested by the disease rather than someone who is bored by it! I hope these blogs will inform, educate and interest people in all the many and various subtype of lymphoma. I hope it will be accessible to patients but also of interest trainees and more senior clinicians. 

Lymphoma in simple terms is a cancer of the adaptive immune system. In particular, the cells of adaptive immune response - lymphocytes - have become cancerous and grow and divide in a poorly controlled way.  Lymphocytes (and we have 2 main types - B lymphocytes and T lymphocytes) coordinate and effect the immune response to many different micro-organisms. B lymphocytes are involved in the production of antibodies and are vital for fighting various bacteria and viruses. Certain types of B-cells (memory B cells) also enable the adaptive immune system to have a memory so it can respond faster second time around. T-lymphocytes can be thought of as the conductors of the immune orchestra, coordinating the immune response. Certain subtypes however kill infected cells whilst other subtypes actually damp down immune responses. 

The majority of lymphomas we see in the UK, Europe and the US are B-cell lymphomas with T-cell lymphomas making up < 10% of cases. This is because during their life-time B-cells have to transit a structure within lymph nodes called the germinal centre. Here, 2 forms of physiological DNA damage occur. Class switch recombination involves a double strand DNA break and results in a change in the subclass of antibody. Somatic hypermutation involves single base-pair mutations in an attempt to refine the specificity of the antibody being produced. In order for this to happen quickly in response to micro-organisms, mechanisms to identify damaged DNA (such as p53 expression) are repressed. This makes the germinal centre a dangerous place for B-cells as if these genetic changes go wrong they are not recognised. If they affect genes that can induce cancer (oncogenes) then normal healthy lymphocytes can turn into lymphoma cells. 

There are 2 broad categories of lymphoma: Hodgkin and non-Hodgkin lymphoma. Thomas Hodgkin was a pathologist at Guys hospital in London in the 19th century and described the first cases of what became known as Hodgkin Lymphoma (although some of his original cases turned out to have TB instead!). I won't go into the details of the different types in this blog but suffice to say Hodgkin lymphoma predominantly affects young people whereas non-Hodgkin lymphoma increases in incidence as you get older. There are high and low grade versions of non-Hodgkin lymphoma. 

I hope you enjoy these posts and find them interesting. I'm not sure yet what shape they'll take and I would very much appreciate feedback or suggestions for future topics.